Applying GIS and population genetics for managing livestock insect pests: case studies of tsetse and screwworm flies.

The Food and Agriculture Organization of the United Nations (FAO) and the International Atomic Energy Agency (IAEA) have supported a Co-ordinated Research Project (CRP) on 'Applying GIS and population genetics for managing livestock insect pests'. This six-year CRP (2008-2013) focused on research aimed at under-pinning the Area-Wide Integrated Pest Management (AW-IPM) of populations of tsetse and screwworm flies, and this introductory paper to the Special Issue integrates the findings of the CRP participants and discusses them in a broader context. The tools and techniques for mapping and modelling the distributions of genetically-characterised populations of tsetse and screwworm flies are increasingly used by researchers and managers for more effective decision-making in AW-IPM programmes, as illustrated by the reports in this Special Issue. Currently, the insect pests are often characterized only by neutral genetic markers suitable for recognizing spatially isolated populations that are sometimes associated with specific environments. Two challenges for those involved in AW-IPM are the standardization of best practice to permit the efficient application of GIS and genetic tools by regional teams, and the need to develop further the mapping and modelling of parasite and pest phenotypes that are epidemiologically important.

Comparative validation of computer programs for haplotype frequency estimation from donor registry data.

Estimation of human leukocyte antigen (HLA) haplotype frequencies from unrelated stem cell donor registries presents a challenge because of large sample sizes and heterogeneity of HLA typing data. For the 14th International HLA and Immunogenetics Workshop, five bioinformatics groups initiated the 'Registry Diversity Component' aiming to cross-validate and improve current haplotype estimation tools. Five datasets were derived from different donor registries and then used as input for five different computer programs for haplotype frequency estimation. Because of issues related to heterogeneity and complexity of HLA typing data identified in the initial phase, the same five implementations, and two new ones, were used on simulated datasets in a controlled experiment where the correct results were known a priori. These datasets contained various fractions of missing HLA-DR modeled after European haplotype frequencies. We measured the contribution of sampling fluctuation and estimation error to the deviation of the frequencies from their true values, finding equivalent contributions of each for the chosen samples. Because of patient-directed activities, selective prospective typing strategies and the variety and evolution of typing technology, some donors have more complete and better HLA data. In this setting, we show that restricting estimation to fully typed individuals introduces biases that could be overcome by including all donors in frequency estimation. Our study underlines the importance of critical review and validation of tools in registry-related activity and provides a sustainable framework for validating the computational tools used. Accurate frequencies are essential for match prediction to improve registry operations and to help more patients identify suitably matched donors.

Estimating unbiased haplotype frequencies from stem cell donor samples typed at heterogeneous resolutions: a practical study based on over 1 million German donors.

The human leukocyte antigen (HLA) distribution in donor registry data is typically nonrandom as, mostly for economical reasons, typing additional loci or resolving ambiguities is selectively performed based on the previously known HLA type. Analyzing a sample of over 1 million German stem cell donors, we practically show the extent of the bias caused by the restriction of the input data for HLA haplotype frequency (HF) estimation to subsets selected according to their higher HLA typing resolution and, conversely, the correctness of estimates based on unselected data with a methodology suitable for heterogeneous resolution. We discuss algorithmic aspects of this approach and, also because of the sample size, provide some new insights into the distribution of HLA-DRB1 alleles in the German population and the application of HFs in unrelated donor search.

Enabling technologies to improve area-wide integrated pest management programmes for the control of screwworms.

The economic devastation caused in the past by the New World screwworm fly Cochliomyia hominivorax (Coquerel) (Diptera: Calliphoridae) to the livestock industry in the U.S.A., Mexico and the rest of Central America was staggering. The eradication of this major livestock pest from North and Central America using the sterile insect technique (SIT) as part of an area-wide integrated pest management (AW-IPM) programme was a phenomenal technical and managerial accomplishment with enormous economic implications. The area is maintained screwworm-free by the weekly release of 40 million sterile flies in the Darien Gap in Panama, which prevents migration from screwworm-infested areas in Columbia. However, the species is still a major pest in many areas of the Caribbean and South America and there is considerable interest in extending the eradication programme to these countries. Understanding New World screwworm fly populations in the Caribbean and South America, which represent a continuous threat to the screwworm-free areas of Central America and the U.S.A., is a prerequisite to any future eradication campaigns. The Old World screwworm fly Chrysomya bezziana Villeneuve (Diptera: Calliphoridae) has a very wide distribution ranging from Southern Africa to Papua New Guinea and, although its economic importance is assumed to be less than that of its New World counterpart, it is a serious pest in extensive livestock production and a constant threat to pest-free areas such as Australia. In the 1980s repeated introductions and an expansion of Old World screwworm populations were reported in the Middle East; in the 1990s it invaded Iraq and since late 2007 it has been reported in Yemen, where a severe outbreak of myiasis occurred in 2008. Small-scale field trials have shown the potential of integrating the SIT in the control of this pest and various international organizations are considering using the release of sterile insects as part of an AW-IPM approach on a much wider scale. Wohlfahrtia magnifica (Schiner) (Diptera: Sarcophagidae) is a screwworm of temperate regions, which, although of limited agricultural importance, has invaded several new locations in the past few years. This special issue reports on the results of a 6-year project funded by the Joint Food and Agriculture Organization of the United Nations/International Atomic Energy Agency (FAO/IAEA) Programme of Nuclear Techniques in Food and Agriculture entitled 'Enabling Technologies for the Expansion of the SIT for Old and New World Screwworm'. A major goal of the project was to better understand population genetic variation in screwworms as an aid to the identification of isolated populations. The project also addressed issues related to genetic sexing, cuticular hydrocarbons, population dynamics, genetic transformation and chromosome analysis.

Assessing the state of population health by age-adjusted life expectancies.

OBJECTIVES: A gain in life expectancy of a population is commonly interpreted as an effect of improved health care. After the reunion of Germany in 1990 life expectancy at birth grew extremely in the new federal states. Within one decade after reunion the new federal states had a gain in life expectancy of about five years while the gain in the old federal states was only about two years. METHODS: It has been widely argued that this phenomenon is caused by an obviously improved public health service and environmental protection or even by an increased social status in the new federal states. On the other hand, the median population age grew rapidly in the new federal states, caused by a dramatic reduction of the birth rate as well as a high emigration rate of young people. Using real time series for three selected federal states and for the total Federal Republic of Germany, it is derived that most of the gain in life expectancy is explained by population ageing. RESULTS: An elementary probabilistic procedure is proposed allowing for estimating the amount in life expectancy not attributable to population ageing. CONCLUSIONS: The age-adjusted life expectancy can be regarded as an unbiased measure of a populations' state of health that stays comparable both over time and across countries.

Expression of early placenta insulin-like growth factor in breast cancer cells provides an autocrine loop that predominantly enhances invasiveness and motility.

Early placenta insulin-like growth factor (EPIL) is expressed by a subpopulation of the Her2-positive SKBR3 breast cancer cell line displaying high motility and transendothelial invasiveness in vitro, as recently shown by our group. As a consequence of this, we established cellular models by generating an EPIL-overexpressing SKBR3 cell line, knocked down EPIL by adding specific small interfering RNA (siRNA) to those cells and produced EPIL-enriched and depleted serum-free culture media. EPIL-expressing cells as well as EPIL-induced SKBR3 cells acquired a high capacity for transendothelial invasiveness. We observed a thin and outspread morphology caused by enhanced formation of lamellipodia, i.e. protrusions in the initial phase of motility. In parallel, Her2-positive MDAHer2 breast cancer cells also showed increased invasiveness when induced by EPIL-conditioned medium. A downstream signaling impact of EPIL could be observed in the form of reduced phosphorylation of Her2, erk1/2 and akt, while phospholipase Cgamma1 phophorylation remained unaffected. As an in vivo model for highly motile tumor cells, Paget's disease of the nipple showed simultaneous EPIL and Her2 expression upon immunohistochemical examination using specific antibodies. Such experimental data have been translated to a clinical setting by using a prognostic tissue microarray established from 603 breast cancer cases. Survival data analysis found a significant association between expression levels of EPIL and 5-year overall survival that was dose dependent: EPIL (negative) 84%, EPIL (moderately positive) 77%, EPIL (strongly positive) 48% (P < 0.005). One particular subgroup (7.6% of the cases with full clinical records) that comprised tumors simultaneously expressing EPIL and Her2 represented patients with the poorest 5-year overall survival. The results suggested that EPIL might be a cancer cell-produced growth factor that influences lateral Her2 signaling. Moreover, EPIL may be induced by factors apart from Her2 and may independently provide signaling for cancer invasion and motility.

[Expression of early placenta insulin-like growth factor (EPIL) in breast cancer cells provides an autocrine loop with enhancement of predominantly HER-2-related invasivity]. / Die Expression des "Early Placenta Insulin-like Wachstumsfaktor" (EPIL) stimuliert über einen autokrinen Mechanismus die HER-2-assoziierte Invasivität von Brustkrebszellen.

AIMS: Recently, we were able to show that the expression of early placenta insulin like growth factor (EPIL) is expressed by highly motile HER-2-positive breast cancer cells in vitro (Brandt et al., Cancer Res. 2002) in Paget cells in vivo and indicates a poor clinical prognosis, irrespectively of other prognostic factors. METHODS: In order to demonstrate the interplay between HER-2 and Epil we established a cellular model for high simultaneous Epil and HER-2 expression. The HER-2-positive breast cancer cell line SKBR3 was modified with an EPIL expression vector. In addition, an assay for the knockdown of EPIL-expression via siRNA was established. Erk1/2 expression was measured via Western Blot. The phenotype of the viable cells was determined by laser scan microscopy. RESULTS: Epil overexpression in SKBR3 cells resulted in fast and frequent protrusion formation of the cells shown by laser scan microscopy. The cells were further characterized by a significantly increased invasiveness, which could be reversed by Epil specific siRNA treatment. Increased invasiveness and morphological changes were associated with a decreased erk1/2 phosphorylation. CONCLUSIONS: These data further supports the assumption that EPIL might provide an autocrine loop in HER-2-positive breast cancer cells that enforce metastasis, conceivably escape from adjuvant therapy and in consequence poor clinical outcome. A tight interaction between HER-2 and EPIL in invasive breast cancer cells is therefore likely. The exact mechanims remain to be elucidated.

[A population-based survey of critical care]. / Eine bevölkerungsbezogene Erhebung zur intensiv-medizinischen Versorgung.

OBJECTIVES: Results of a population-based survey of critical care in a German state are presented. The indication for critical care was derived using the APACHE-II score,which measures the physiologic state of patients, and the TISS-28 score as a measure for expenditure of critical care. METHODS: During 3 months all adult patients of intensive care units in Saarland, a German state with 1.08 million residents,were included. All kinds of hospitals were involved. Completeness and validity of data are proved. RESULTS: The TISS score was registered daily on 13,391 adult patients with 54,503 days, the APACHE score during admission and discharge of intensive care units only. The correlation between the scoring-systems and indication, kind of care (critical care vs. intermediate care), kind of hospital, and ICD-10 diagnoses is analysed in this paper. CONCLUSIONS: In this study the population-based critical care in a state is analysed the first time. It completes previously published studies,which were performed at the level of hospitals and departments.

Ordinal classification in medical prognosis.

OBJECTIVES: Medical prognosis is commonly expressed in terms of ordered outcome categories. This paper provides simple statistical procedures to judge whether the predictor variables reflect this natural ordering. METHODS: The concept of stochastic ordering in logistic regression and discrimination models is applied to naturally ordered outcome scales in medical prognosis. RESULTS: The ordering stage is assessed by a data-generated choice between ordered, partially ordered, and unordered models. The ordinal structure of the outcome is particularly taken into consideration in the construction of allocation rules and in the assessment of their performance. The specialized models are compared to the unordered model with respect to the classification efficiency in a clinical prognostic study. CONCLUSIONS: It is concluded that our approach offers more flexibility than the widely used cumulative-odds model and more stability than the multinomial logistic model. The procedure described in this paper is strongly recommended for practical applications to support medical decision-making.

EEG gamma-band phase synchronization between posterior and frontal cortex during mental rotation in humans.

The main purpose of the present paper was: (1) to study the phase synchronization pattern in the gamma-band while performing the classical Shepard-Metzler task of mental rotation; (2) to investigate the role of musical training; and (3) to study hemispheric differences in the degree of synchronization during mental rotation. Multivariate electroencephalograph signals from 20 male subjects (ten musicians and ten non-musicians) were recorded while performing the mental rotation task and also at resting condition. Phase synchronization was measured by a recent index, mean phase coherence. It was found that synchronization between frontal cortex and right parietal cortex was significantly increased during mental rotation with respect to rest, whereby musicians showed significantly higher degrees of synchronization than non-musicians. Left hemispheric dominance in the degree of phase synchronization, stronger in the posterior right parietal and occipital regions, was observed in musicians. Right hemispheric dominance was generally observed in non-musicians.

Methods of ordinal classification applied to medical scoring systems.

Scoring systems are used in nearly all fields of medicine for evaluation of the state of a disease. The prediction performance of scoring systems with respect to an ordinal outcome scale is investigated, based on grouped continuous logistic models as well as on an extension of the stereotype logistic regression model. The latter is a canonical approach, which allows assessment of properties of outcome categories such as partial and total ordering, distinguishability and allocatability. The approach is applied to a data set of patients with injuries of the head.

[Validation of the prognostic accuracy of neurosurgical admission scales after rupture of cerebral aneurysms]. / Validierung der prognostischen Aussagekraft neurochirurgischer Aufnahmeskalen nach Rupturen zerebraler Aneurysmen.

The course of 185 patients operated for a ruptured intracranial aneurysm at the University of Saarland between 1991 and 1993 has been followed up. The main emphasis of the investigation was placed on the scrutiny of the coma scales on admission (Hunt & Hess-Scale, Glasgow Coma Scale and WFNS-Scale [= World Federation of Neurological Surgeons]) with regard to the outcome. Outcome was defined as the patients' state six months after aneurysm rupture according to the Glasgow Outcome Scale. The sensitivities, specifities and predictive values of almost all scale grades were poor. The Hunt&Hess-Scale was the one with the best correlation. By half the patients with the worst scale grades on admission had a good outcome. A gradation of the outcome with regard to the middle admission grades has not been identified. These observations have been demonstrated by using ROC (Receiver Operating Characteristic)-curves. The admission scales are not suitable to give a definite prognosis and do not justify any decision neither pro nor contra an operation. A lot of parameters besides the neurological findings have an effect on the prognosis. Additionally, unexpected complications may occur in the pre- and postoperative phase. The score values determined at the day of operation have shown a more precise prognosis than the values determined immediately after hospitalization. Therefore the evaluation of the most relevant phase could improve the prognostic value of the scales.

Medical information processing: an interactive course for the Internet.

Medical students in Germany have to study the basics of medical information processing within a special curriculum which is part of the ecological course. This curriculum offers an introduction to principles of medical informatics. Starting with a conventional textbook, a computer-based training (CBT) program has been developed using the technologies of the internet and the World Wide Web (WWW). Features of the program include a well structured presentation of the information within the software and a high degree of interactivity. Early experiences suggest that this program enhances the learning in the domain of medical information processing. The program may be viewed via the URL: htfp.//www.med-rz.uni-sb.de/med_fak/imbei/pro jekt.

Multivariate logistic analysis of dose-effect relationship and latency of radiomyelopathy after hyperfractionated and conventionally fractionated radiotherapy in animal experiments.

PURPOSE: We examined in rats whether the radiation tolerance of spinal cord is enhanced by using hyperfractionated radiotherapy compared to a conventional schedule. Higher tolerable doses to the spinal cord would allow dose escalation to the tumor and thus possibly lead to higher cure rates, especially in tumors with high cell proliferation. METHODS AND MATERIALS: Cervical spinal cord of 276 healthy rats was irradiated over 6 weeks hyperfractionally with single doses ranging from 0.75-2.5 Gy up to total doses ranging from 45-150 Gy (60 fractions) and conventionally with single doses of 1.5-4.0 Gy up to total doses of 45-120 Gy (30 fractions). The rats were examined neurologically and sacrificed when paralysis of the hind legs occurred. After fixation, spinal cord was removed and examined histologically. Dose-effect relationship and latency from the beginning of radiotherapy to the onset of paralysis were computed and analyzed using a multivariate logistic regression model. RESULTS: The model fitted the observed data excellently. There were highly significant effects both for the dose level and for the treatment regimen. Latency analysis showed earlier and more intense acute side effects after hyperfractionation but radiomyelopathy occurred markedly later. CONCLUSIONS: The sparing effect of hyperfractionation on spinal cord as predicted by radiobiologists could be confirmed in our experiments. Thus, it seems possible to escalate tumor doses using hyperfractionation without enhanced risk to spinal cord but with higher probability of tumor cure.

Assessment of grading systems in medicine.

Criteria allowing for a quality assessment of grading systems in medicine are investigated and explained using a real data set.

Epidemiologic assessment of risks of adverse reactions associated with intermittent exposure.

Measures of risk of adverse reactions, such as the absolute risk, the relative risk, and the excess risk, are analyzed for individuals who are exposed occasionally for periods of varying duration. This type of exposure is of particular importance for the epidemiologic assessment of drug safety. A Poisson point process model that allows for the simultaneous consideration of concomitant factors is derived for the estimation of the hazard rates. The model can judge acute adverse reactions and is applicable not only for rare risks since an undesired effect may occur repeatedly for an individual. Hazard estimation is achieved with the aid of the maximum likelihood method for several sampling designs, such as cohort studies, case-cohort studies, and case studies. In the latter design only those individuals who have had an adverse reaction during the time of observation are considered for hazard estimation. An application to the analysis of wound-healing impairments is given.

Design and analysis of drug safety studies, with special reference to sporadic drug use and acute adverse reactions.

A methodological approach for analysis of drug safety data which permits the calculation of risk measures for intermittent exposures and acute adverse reactions is presented. This method allows for the observation of exposures that are temporary and which may be of varying lengths, as in the application of analgesics. Risk measures are determined using the relative risk and the excess risk to assess drug safety. The latter has important public health policy significance for decision making about the safety of a drug. The model depends on a simple counting process and allows for the consideration of concomitant variables which can likewise exert an influence on the absolute risk. Hazard estimates are derived by the maximum likelihood method. Three possible approaches to the planning and analysis of studies of drug safety are discussed: cohort studies, case-cohort studies, and case studies. The case study represents an approach which requires only data from the individuals in which an adverse reaction has occurred. The different sampling designs are illustrated using data from a study investigating the etiology of wound healing disorders.