Missing life stories. The narratives of palliative patients, parents and physicians in paediatric oncology.

Illness narratives have become very popular. The stories of children, however, are rarely ever studied. This paper aims to provide insight into how children, parents and physicians make sense of progressive childhood cancer. It also explores how this meaning-giving process interacts with cultural dominant stories on cancer and dying. The presented data come from 16 open-ended face-to-face interviews with palliative paediatric patients, their parents and physicians. The interviews were carried out in eight paediatric oncology centres in Switzerland. Data analysis followed Arthur Frank's dialogical narrative analysis. Quest narratives were relatively rare compared to both chaos and restitution stories. All participants welcomed chaos stories as a liminal haven between quest and restitution. The possibility that the child could die was either ignored or briefly contemplated, but then immediately pushed away. Except for one patient, children never directly addressed the topic of death. The way in which death was presented raises important questions about how the social discourse on dying is framed in terms of choice, autonomy and individuality. This discourse not only determines the way in which children and adults relate to the minor's death, it also constitutes an obstacle to children's participation in decision-making.

Ramsey spectroscopy of high-contrast CPT resonances with push-pull optical pumping in Cs vapor.

We report on the detection of high-contrast and narrow Coherent Population Trapping (CPT) Ramsey fringes in a Cs vapor cell using a simple-architecture laser system. The latter allows the combination of push-pull optical pumping (PPOP) and a temporal Ramsey-like pulsed interrogation. An originality of the optics package is the use of a single Mach-Zehnder electro-optic modulator (MZ EOM) both for optical sidebands generation and light switch for pulsed interaction. Typical Ramsey fringes with a linewidth of 166 Hz and a contrast of 33 % are detected in a cm-scale buffer-gas filled Cs vapor cell. This technique could be interesting for the development of high-performance and low power consumption compact vapor cell clocks based on CPT.

Changes in species richness and spatial distribution of mosquitoes (Diptera: Culicidae) inferred from museum specimen records and a recent inventory: a case study from Belgium suggests recent expanded distribution of arbovirus and malaria vectors.

Mosquito (Diptera: Culicidae) distribution data from a recent inventory of native and invading mosquito species in Belgium were compared with historical data from the period 1900-1960 that were retrieved from a revision of the Belgian Culicidae collection at the Royal Belgian Institute of Natural Sciences. Both data sets were used to investigate trends in mosquito species richness in several regions in Belgium. The relative change in distribution area of mosquito species was particularly important for species that use waste waters and used tires as larval habitats and species that recently shifted their larval habitat to artificial larval habitats. More importantly, several of these species are known as vectors of arboviruses and Plasmodium sp. and the apparent habitat shift of some of them brought these species in proximity to humans. Similar studies comparing current mosquito richness with former distribution data retrieved from voucher specimens from collections is therefore encouraged because they can generate important information concerning health risk assessment at both regional and national scale.

Nationwide inventory of mosquito biodiversity (Diptera: Culicidae) in Belgium, Europe.

To advance our restricted knowledge on mosquito biodiversity and distribution in Belgium, a national inventory started in 2007 (MODIRISK) based on a random selection of 936 collection points in three main environmental types: urban, rural and natural areas. Additionally, 64 sites were selected because of the risk of importing a vector or pathogen in these sites. Each site was sampled once between May and October 2007 and once in 2008 using Mosquito Magnet Liberty Plus traps. Diversity in pre-defined habitat types was calculated using three indices. The association between species and environmental types was assessed using a correspondence analysis. Twenty-three mosquito species belonging to traditionally recognized genera were found, including 21 indigenous and two exotic species. Highest species diversity (Simpson 0.765) and species richness (20 species) was observed in natural areas, although urban sites scored also well (Simpson 0.476, 16 species). Four clusters could be distinguished based on the correspondence analysis. The first one is related to human modified landscapes (such as urban, rural and industrial sites). A second is composed of species not associated with a specific habitat type, including the now widely distributed Anopheles plumbeus. A third group includes species commonly found in restored natural or bird migration areas, and a fourth cluster is composed of forest species. Outcomes of this study demonstrate the effectiveness of the designed sampling scheme and support the choice of the trap type. Obtained results of this first country-wide inventory of the Culicidae in Belgium may serve as a basis for risk assessment of emerging mosquito-borne diseases.

e-Surveillance in animal health: use and evaluation of mobile tools.

In the last decade, mobile technology offered new opportunities and challenges in animal health surveillance. It began with the use of basic mobile phones and short message service (SMS) for disease reporting, and the development of smartphones and other mobile tools has expanded the possibilities for data collection. These tools assist in the collection of data as well as geo-referenced mapping of diseases, and mapping, visualization and identification of vectors such as ticks. In this article we share our findings about new technologies in the domain of animal health surveillance, based on several projects using a wide range of mobile tools, each with their specific applicability and limitations. For each of the tools used, a comprehensive overview is given about its applicability, limitations, technical requirements, cost and also the perception of the users.The evaluation of the tools clearly shows the importance of selecting the appropriate tool depending on the envisaged data to be collected. Accessibility, visualization and cost related to data collection differ significantly among the tools tested. This paper can thus be seen as a practical guide to the currently available tools.

Bionomics of the established exotic mosquito species Aedes koreicus in Belgium, Europe.

Adults of an exotic mosquito, Aedes (Finlaya) koreicus (Edwards) (Diptera: Culicidae) were identified by morphology and genotyping from one site in Belgium in 2008. In late summer of that year, the occurrence of adults and immature stages reconfirmed its presence. This is the first record of this species outside its native range and in particular in Europe. Two subsites of the original location were prospected from April until October 2009 with different traps to evaluate the extent of its presence and establishment in the area and to understand the dynamics of the species' population. Next to Ae. koreicus, 15 other mosquito species were collected. Adult individuals of Ae. koreicus were found from May to September and larvae were still found early October. Larvae were mainly retrieved from artificial containers both in 2008 as in 2009. Containers with eggs and/or larvae were found up to 4 km away from the initial location, indicating the species is spreading locally. Though the introduction route is unknown, it may have occurred via international trade as a large industrial center was located nearby. A comparison of different climatic variables between locations in Belgium with Ae. koreicus and putative source locations in South Korea, revealed similarities between winter temperatures and the number of freezing days and nights in four consecutive years (2004-2008), while humidity and precipitation values differed strongly. The introduction of a new potential disease vector into Europe seems to be a result of proper entrance points, created by intense worldwide trade and suitable environmental conditions.

Geographic distribution of the invasive cattle tick Rhipicephalus microplus, a country-wide survey in Benin.

The cattle tick Rhipicephalus microplus is currently invading the West African region, and little information is available on the spread of this exotic tick in this region. We set out a country-wide field survey to determine its current distribution in Benin. Ticks were collected on cattle from 106 farms selected by random sampling covering all regions of the country. Rhipicephalus annulatus was found on 70 % of all farms, R. decoloratus on 42 %, R. geigyi on 58 %, and R. microplus on 49 %. There is a clear geographic separation between the indigenous Rhipicephalus species and R. microplus. Rhipicephalus annulatus occurs mainly in the northern departments, but it was also observed in lower numbers in locations in the south. The presence of R. decoloratus is limited to the northern region, and in most locations, this tick makes up a small proportion of the collected ticks. The tick R. geigyi tends to be dominant, but occurs only in the four northern departments. The observations concerning R. microplus are entirely different, this species occurs in the southern and central region. The results of this survey confirm the invasive character and displacement properties of R. microplus, since in less than a decade it has colonized more than half of the country and has displaced indigenous ticks of the same genus in many of the sampled locations.

AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor.

The bicyclam AMD3100 (formula weight 830) blocks HIV-1 entry and membrane fusion via the CXCR4 co-receptor, but not via CCR5. AMD3100 prevents monoclonal antibody 12G5 from binding to CXCR4, but has no effect on binding of monoclonal antibody 2D7 to CCR5. It also inhibits binding of the CXC-chemokine, SDF-1alpha, to CXCR4 and subsequent signal transduction, but does not itself cause signaling and has no effect on RANTES signaling via CCR5. Thus, AMD3100 prevents CXCR4 functioning as both a HIV-1 co-receptor and a CXC-chemokine receptor. Development of small molecule inhibitors of HIV-1 entry is feasible.

Human-induced expanded distribution of Anopheles plumbeus, experimental vector of West Nile virus and a potential vector of human malaria in Belgium.

For the majority of native species, human-created habitats provide a hostile environment that prevents their colonization. However, if the conditions encountered in this novel environment are part of the fundamental niche of a particular species, these low competitive environments may allow strong population expansion of even rare and stenotopic species. If these species are potentially harmful to humans, such anthropogenic habitat alterations may impose strong risks for human health. Here, we report on a recent and severe outbreak of the viciously biting and day-active mosquito Anopheles plumbeus Stephens, 1828, that is caused by a habitat shift toward human-created habitats. Although historic data indicate that the species was previously reported to be rare in Belgium and confined to natural forest habitats, more recent data indicate a strong population expansion all over Belgium and severe nuisance at a local scale. We show that these outbreaks can be explained by a recent larval habitat shift of this species from tree-holes in forests to large manure collecting pits of abandoned and uncleaned pig stables. Further surveys of the colonization and detection of other potential larval breeding places of this mosquito in this artificial environment are of particular importance for human health because the species is known as a experimental vector of West Nile virus and a potential vector of human malaria.

Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4.

Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as BaL, ADA, JR-CSF, and SF-162 in human peripheral blood mononuclear cells, the compound was completely inactive. Because of the specific and potent inhibitory effect of AMD3100 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-tropic viruses. AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry. It did not inhibit the binding of the biotinylated CC-chemokine macrophage inflammatory protein (MIP) 1alpha or MIP-1beta, ligands for the chemokine receptor CCR5 (the main coreceptor for M-tropic viruses). In addition, AMD3100 completely blocked (a) the Ca2+ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell-derived factor 1alpha, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca2+ flux induced by the CC-chemokines MIP-1alpha, regulated on activation normal T cell expressed and secreted (RANTES; also a ligand for CCR5), or monocyte chemoattractant protein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca2+ fluxes by itself. The bicyclams are, to our knowledge, the first low molecular weight anti-HIV agents shown to act as potent and selective CXCR4 antagonists.

Viral infection and host defense.

Double-stranded RNA, made as an intermediary substance in the replication of most, if not all, viruses, may play a much more important role in the pathogenesis and the recovery from virus infections than has hitherto been suspected. Apparently, dsRNA is used by both the challenge virus and the host cell in an attempt to gain "molecular control." Double-stranded RNA exerts a set of effects, which may be well balanced, not only at the level of the individual cell but also at the complex assemblage of these cells termed the organism (Fig. 1). In the cell, interferon synthesis is triggered, although interferon mRNA translation may not occur if dsRNA shuts off protein synthesis too quickly. In the whole organism, the disease severity will depend on how certain toxic reactions evoked by infection (such as cell necrosis and fever) are counterbalanced by an increase in the host defense mechanisms (for example, immune responsiveness and interferon production). Many aspects of the response, relating to either progress of, or recovery from, the disease, can be explained on the basis of a dsRNA. In addition to drawing attention to the biodynamic role of dsRNA, our hypothesis suggests specific experimental vectors designed to enhance our information on the molecular basis of the morbid process which occurs with viral infection. Finally, we suggest that, although the dsRNA molecule may be viewed as a rather simple unit structure, the opportunity for further diversity in the biological activity of a given dsRNA molecule always exists. Namely, each deviation from a perfectly double-helical arrangement introduces the possibility for emphasizing one biological reactivity at the expense of another. This latter structure-activity property may partially account for the extreme apparent diversity, commonly encountered, in the presentations of virologic illness. Appendix note added in proof. Subsequent to submission of this text, we have found that the potent mitogen effect of dsRNA for lymphocytes (murine and human) is also exquisitively sensitive to the fidelity in base pairing of the input polymer pair (59). For example, infrequent "loops" (one nucleotide per 20 base pairs) in an otherwise perfectly helical rI(n) (.) rC(n) molecule [for example, rI(n) (.) r(C(19,)U)(n)] strongly changes its mitogenic properties. This observation, which supports our thesis that a "fine structure" term can be developed for other reactions triggered by dsRNA's in biological systems, emphasizes that diverse biological effects may be encountered with an ostensibly uniform family of dsRNA's.

[Interferon induction increased through chemical modification of a synthetic polyribonucleotide].

The alternating copolymer riboadenylic-ribouridylic acid gained asignificant increase in ability to stimulate interferon production (2-to 20-fold) and cellular resistance (100-to 10,000-fold) both in vitro and in vivo upon substitution of phosphate by thiophosphate groups. The resulting nucleotide analog was also 10 to 100 times less sensitive to degradation by pancreatic ribonuclease, as determined byresidual antiviral activity.

Antiviral activity of polyribocytidylic acid in cells primed with polyriboinosinic acid.

Separate administration of polyribocytidylic acid [poly(rC)] and polyriboinosinic acid [poly(rI)] to cell cultures in vitro resulted in an antiviral activity identical to or greater than that resulting from addition of the poly(rI) * poly(rC) complex. Priming of cells with poly(rI), followed by treatment with poly(rC), gave a consistently greater antiviral activity than poly(rI) * poly(rC) itself. This priming effect was obtained in several cell cultures challenged with different viruses. In vivo, the antiviral activity of poly(rI) * poly(rC) was only partially restored if poly(rI) and poly(rC) were injected separately; prior injection of poly(rI) proved superior in restoring this antiviral activity as compared to prior injection of poly(rC).

(S)-9-(2,3-Dihydroxypropyl)adenine: An Aliphatic Nucleoside Analog with Broad-Spectrum Antiviral Activity.

(S)-9-(2,3-Dihydroxypropyl)adenine, a novel nucleoside analog, the sugar moiety of which is replaced by an aliphatic chain, inhibits the replication in vitro of several DNA and RNA viruses, including vaccinia, herpes simplex (types 1 and 2), measles, and vesicular stomatitis. It is also effective in vivo in reducing the mortality rate of mice inoculated intranasally with vesicular stomatitis virus.

(S)-9-(2,3-Dihydroxypropyl)adenine: an aliphatic nucleoside analog with broad-spectrum antiviral activity.

(S)-9-(2,3-Dihydroxypropyl)adenine, a novel nucleoside analog, the sugar moiety of which is replaced by an aliphatic chain, inhibits the replication in vitro of several DNA and RNA viruses, including vaccinia, herpes simplex (types 1 and 2), measles, and vesicular stomatitis. It is also effective in vivo in reducing the mortality rate of mice inoculated intranasally with vesicular stomatitis virus.

Interferon induction: tool for establishing interactions among homopolyribonucleotides.

Hitherto unrecognized interactions between homopolyribonucleotides and complexes thereof are suggested by interferon induction data obtained in a highly sensitive assay system of primary rabbit kidney cell cultures superinduced by metabolic inhibitors.

High efficiency latency and activation of herpes simplex virus in human cells.

Herpes simplex virus (HSV) exists in humans in a latent form that can be activated. To characterize the molecular basis of the cell-virus interactions and to analyze the state of the latent HSV genome, an in vitro model system was established. In this system a large fraction of the latently infected cells contain an HSV genome that can be activated. Cell survival was reduced minimally after repression of high multiplicity HSV type 1 (HSV-1) infection of human fibroblast cells with (E)-5-(2-bromovinyl)-2'-deoxyuridine in combination with human leukocyte interferon (IFN-alpha). A minimum of 1 to 3 percent of the surviving cells contained an HSV genome that could be activated either by human cytomegalovirus superinfection or reduction in incubation temperature.

Antiviral agents acting as DNA or RNA chain terminators.

Nucleoside or nucleotide analogue inhibitors of viral replication almost act as chain terminators during DNA (DNA- and retroviruses) or RNA (RNA viruses) synthesis. Following intracellular phosphorylation, by viral and/or cellular kinases, the 5'-triphosphate metabolites (or 2'-diphosphate metabolites in the case of acyclic nucleoside phosphonate analogues) compete with the natural substrate in the DNA or RNA polymerization reaction. Obligatory chain terminators (e.g., acyclovir) do not offer the 3'-hydroxyl function at the riboside moiety of the molecule. Nucleoside analogues that possess a hydroxyl function at a position equivalent of the 3'-hydroxyl position may act as chain terminators if this hydroxyl group is conformationally constrained (e.g., ganciclovir) or sterically hindered to enter into a phosphodiester linkage with the incoming nucleotide. In case that the 3'-hydroxylgroup is correctly positioned, chain elongation may be hampered through steric hindrance from neighboring substituents (e.g., 2'-C-methyl or 4'-azido nucleoside inhibitors of HCV replication). Here, we review the molecular mechanism of action and the clinical applications of the nucleosides and nucleotides acting as chain terminators. A further discussion of clinical applications in combination therapy can be found in Chap. 12.

Interferon: the quintessence of a quinquagenarian.

Now more than 50 years after interferon was discovered, in 1957, by Isaacs and Lindenmann, this quinquagenarian has evidently come to age. Its major indications for clinical use are, for interferon-alpha, now mostly used in its pegylated form, the treatment of chronic hepatitis B and chronic hepatitis C, the latter generally in combination with ribavirin; and for interferon-beta, the treatment of multiple sclerosis (MS). Of quintessence in the 50 years with interferon has been the cloning of interferon-alpha and -beta in 1980, which not only proved its identity, but also laid the basis for its application in the treatment of hepatitis (B and C) and multiple sclerosis, respectively.

The novel primaquine derivatives of N-alkyl, cycloalkyl or aryl urea: synthesis, cytostatic and antiviral activity evaluations.

The novel urea primaquine derivatives 3a-i were prepared by aminolysis of benzotriazolide 2 with the corresponding amine in the presence or absence of triethylamine. Compound 2 was prepared by acylation of primaquine with 1-benzotriazole carboxylic acid chloride. Among all compounds evaluated, the pyridine derivative 3h exhibited the best cytostatic activities against colon carcinoma, human T-lymphocyte and murine leukemia. However, this compound showed also rather marked cytotoxicity towards human normal fibroblasts. The highest selectivity in the inhibitory effects on human malignant tumor cell lines vs. normal fibroblasts was found for ureas 3c, 3d and 3g. Results of broad antiviral evaluation showed that pyridine and phenethyl derivatives of urea 3h and 3g exhibited some selective inhibition against cytomegalovirus.