[Attitudes towards immunization]. / Opinions et réticences face à la vaccination.

PURPOSE: Ever since vaccination was introduced, a minority has been opposed to this practice. Recently however, fear of adverse events and a general questioning of the usefulness of certain vaccines have led to wariness on the part of the broader public. In France, this phenomenon is particularly striking since the hepatitis B vaccination campaign. We wished to analyse the situation by drawing on the results of surveys conducted by the French Institute of Prevention and Health Education (Institut national de prévention et d'éducation pour la santé, INPES) which sought to gain a better understanding of health care professionals' and the general public's attitudes towards immunization. MAIN POINTS: Although the majority of French men and women are convinced of the overall benefit of vaccination in the past, they increasingly question vaccine safety and usefulness today. PERSPECTIVES: In order to prevent further deterioration of the situation, efforts must be made to enhance public and professional awareness as to the stakes involved in the control of vaccine preventable diseases.

[Perceptions of hepatitis B vaccination in France. Analysis of three surveys]. / Perceptions de la vaccination contre l'hépatite B en France. Analyse de trois enquêtes.

BACKGROUND: The main target for hepatitis B vaccination has never been reached, since less than 30% of infants were immunized in 2000. We wished to examine what might explain this situation by surveying attitudes within the general public and among vaccinators. METHODS: We analyzed and compared the data on hepatitis B vaccination from three quantitative surveys conducted by the National Institute of Prevention and Health Education in 2003-2005. RESULTS: Even those physicians (especially pediatricians) who are favorable to hepatitis B immunization do not always apply recommendations; 95% of physicians stated their patients are rather reticent to participate. Regarding the general public, less than half of French adults would be prepared to have their infant immunized against hepatitis B. CONCLUSION: The usefulness of immunizing infants, rather than the absence of adverse events, should be put forth as the main argument in favour of hepatitis B immunization, both for physicians and the larger public.

What is vaccine advocacy? Proposal for a definition and action.

Successful immunization programmes have reduced the burden of a number of infectious diseases on a global scale. Yet, as the fear of sequelae of vaccine-preventable diseases diminishes in the public, the focus of interest has shifted towards true and alleged "side effects". Maintaining confidence in the necessity, tolerability and safety of immunizations is of paramount importance today. This requires, amongst other prerequisites, precise definitions of "adverse events following immunization". In Europe, a collaborative effort named EUSAFEVAC in concert with the globally active "Brighton Collaboration" has been initiated. Volunteers from academic institutions, vaccine licensing authorities, public health institutes, governmental organizations, safety units within the vaccine manufacturing industry as well as practising physicians are working together to achieve this goal.

Human cytosolic and mitochondrial folylpolyglutamate synthetase are electrophoretically distinct. Expression in antifolate-sensitive and -resistant human cell lines.

Folylpolyglutamate synthetase (FPGS) activity in CCRF-CEM human leukemia cells was found in the cytosolic ( approximately 67% of total) and mitochondrial ( approximately 22%) fractions. A polyclonal antipeptide antibody (430Ab) to human FPGS specifically recognized distinct immunoreactive bands ( approximately 60 kDa) present in each subcellular fraction. Human cytosolic FPGS (hcFPGS) migrated more rapidly than mitochondrial FPGS (hmFPGS); their estimated difference in molecular mass was 1 kDa. The human K562 acute nonlymphocytic leukemia and the A253 and FaDu head and neck cancer cell lines also expressed the two FPGS isoforms, and the ratio of hcFPGS to hmFPGS protein in each cell line was similar. Since K562 and A253 cells are intrinsically resistant to pulse methotrexate (MTX) exposure relative to CCRF-CEM and FaDu cells, respectively, because of decreased MTX polyglutamate synthesis (despite having similar levels of total FPGS activity expression), these data suggest that the natural difference in drug sensitivity cannot be explained by compartmentalization of FPGS activity. Higher expression of hmFPGS relative to hcFPGS was observed in some sublines of CCRF-CEM with acquired MTX resistance suggesting that differential expression of the hmFPGS isoform may contribute to MTX resistance caused by decreased FPGS activity.

Warsaw conference on emerging infections in central and eastern Europe.

PIP: On March 28-29, 2000, epidemiologists and microbiologists convened in Warsaw, Poland, to discuss emerging, re-emerging, and drug-resistant infections in central and eastern Europe. Delegates were from the Czech Republic, Greece, Hungary, Latvia, Poland, Romania, Russia, and Yugoslavia, with the exception of the US and the UK and other worst affected countries in central-eastern Europe. It has been documented that the cause of diphtheria epidemics in several countries in the mid-1990s resulted from the breakdown of vaccination campaigns following social dislocation. Currently, diphtheria morbidity has declined through targeted vaccination programs, although fundamental socioeconomic problems continue to threaten public health. Other infectious diseases raised during the conference were the evolution of tuberculosis and HIV/AIDS, which remains largely unpredictable. In addition, the growing incidence of multidrug-resistant tuberculosis is documented in several countries. Among the major problems in tuberculosis control include late diagnosis, nonexistent or erratic drug supplies and unreliable reporting. The syringe ecosystem in both healthcare settings and injecting drug users were singled out as the vectors of sharp increase in HIV/AIDS infection. Throughout the conference, the recurrent theme was on the overriding importance of providing specialized training and the building up of networks of public health specialists.^ieng

Cellular aspects of folate and antifolate membrane transport.

Folates--one carbon carriers--take part in the metabolism of purine, thymidylate and some amino acids. Internalization of these compounds employs several mechanisms of transport systems. Reduced folate carriers and folate receptors play the most important role in this process. The physiological role of these molecules in normal and neoplastic cells is described regarding changes in transport activity and connection of transport systems with resistance to antifolates and cancer development.

[Poland: cholera to typhus, 1831-1950]. / La Pologne: du choléra au typhus, 1831-1950.

In this article devoted to Poland's direct and indirect role in the elaboration of contemporary international health structures and to her reputation as an epidemic reservoir of Europe, we consider how Poland came to be perceived as the cordon sanitaire of the West. Traditionally seen as upholding Western values, in the 19th and 20th centuries the country became increasingly associated with "Eastern plagues"-cholera and then typhus-coming from Russia and which could spread to the rest of Europe if Poland did not manage to contain them. When Poland was reconstituted as a nation-state in 1918, the new country won international recognition through her successful attempts to contain a typhus epidemic sweeping westwards from Russia. The Polish government convened the first European, League sponsored, health conference following the First World War. A Polish doctor, L. RAJCHMAN, was chosen to head up the League of Nations Health Organisation (forerunner of the WHO) and later (1946) founded UNICEF. Finally, we examine the key issue of exanthematous typhus in both world wars, exemplifying how a disease can come to be "ideologized", in this case by Nazi Germany. Typhus was the pretext used- in the name of "public health"-for segregating Polish citizens of Jewish origin and even killing them. Paradoxically, typhus was in the process of being eradicated when the war began and German policy of mass resettlements, sequestration, and starvation only spurred the epidemic they supposedly wished to control.

Synergistic effect of 5-fluorodeoxyuridine and quinazoline antifolates on murine leukemia self-cultured in vitro.

The effect of thymidylate synthase inhibitors, fluorodeoxyuridine (FdUrd) and its two sulphonamide derivatives was examined in the culture of murine leukemia cells -- 5178Y (parental subline) and its fluorodeoxyuridine resistant subline 5178Y/F. A synergistic effect of the antimetabolites on cell survival was observed on exposure of the culture of either line to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mate or 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphoglyci ne. This effect was accompanied by a marked reduction, in both cell lines of intracellular concentration of 5,10-methylenetetrahydro-pteroyl-polyglutamate, although its concentration in the resistant subline was 3 times as high as in the parental line. The inhibitory effect of combined drugs on the cellular pool of folates in 5178Y line depended also on the sequence of drug addition, whereas in the FdUrd resistant line this sequence was without any effect. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by a prior use of FdUrd.

The effects of combined antifolates on inhibition of growth of murine leukemia cells cultured in vitro.

The synergistic effect of trimetrexate (TMTX) and sulphonamide derivatives of quinazoline on the cultured 5178Y murine leukemia cells was examined. On exposure to the slightly inhibitory concentrations of TMTX (0.1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroyl-sulphoglyc ine (DMPDDSF) (0.02 microM) a synergistic inhibitory effect of the antifolates on cell growth was observed. These two drugs in the same combination caused also synergistic inhibition of de novo synthesis of thymidylate in intact cells as measured by tritium release from [5-(3)H]deoxyuridylate. This was accompanied by a marked reduction in intracellular concentration of 5,10-methylenetetrahydro-pteroyl-polyglutamate (5,10CH2H4PteGlu(n)) (0.2 microM) and dihydropteroyl-polyglutamate (0.12 microM). In these conditions de novo biosynthesis of purine was decreased by 50%. These observations show that growth inhibition by combined antifolates is mediated by intracellular depletion of the substrate of thymidylate synthase -- 5,10CH2H4PteGlu(n). The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by DMPDDSF is intensified by prior application of TMTX -- an inhibitor of dihydrofolate reductase.

Effect of combined inhibitors of thymidylate synthase-5-fluorodeoxyuridine and quinazoline antifolates on murine leukemia cells cultured in vitro.

The synergistic effect of two different inhibitors of thymidylate synthase-FdUrd and sulphonamide derivatives on murine leukemia cells-5178Y (parental subline) and 5178Y/F (its fluorodeoxyuridine resistant subline) in culture was examined. Upon the exposure of cultures from both lines to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mine or -glycine a synergistic effect of antimetabolites on cell growth was observed. This was accompanied by a marked reduction in intracellular concentration in both cell lines of 5,10CH2H4PteGlu; the intracellular concentration of 5,10CH2H4PteGlu(n) in the resistant subline was 3 times higher than in parental line. The inhibitory effect of combined drugs on the cellular pool of 5178Y of the two antimetabolites also depends on the sequence of their addition; however in the FdUrd resistant cell-line the dependence on the sequence of the addition was not observed. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by proprior use of FdUrd.

The National Institute of Hygiene and public health in Poland 1918-1939.

As the largest country of the former Eastern bloc, Poland presents an interesting case study for the evolution of public health in Eastern Europe in the twentieth century. This article looks more specifically at the interwar period when an epidemiological institute--created to deal with the epidemic aftermath of the First World War--developed into the National Institute of Hygiene (NIH), still Poland's first and foremost public health institution today. It considers the origins of the Polish hygiene movement, the influence of foreign models on Polish health structures as well as the specificities of the political and economic context of the 1920s and 1930s in relation to health issues. The foundations laid in those years seem to have played a more important role in the improvement of post war health than is commonly believed.

Regulation of folate-dependent enzyme levels in Aspergillus nidulans: studies with regulatory mutants.

The synthesis of folate-dependent enzymes in Aspergillus nidulans appears to be regulated by intracellular pools of homocysteine and methionine. The results are consistent with the view that homocysteine acts as an inducer and methionine as a corepressor, but the molecular mechanism of the regulation is still unknown. Methionine-requiring mutants, metH2 and metD10, apparently allelic, show deregulation of folate-dependent enzymes. Most characteristic of the mutants is a repressed level of folylpolyglutamate synthetase. New mutations suppressing the metH2 lesion which render folate enzymes insensitive to methionine-mediated repression have been isolated. These mutations are likely to identify new regulatory genes in folate metabolism.

2-Thio derivatives of dUrd and 5-fluoro-dUrd and their 5'-monophosphates: synthesis, interaction with tumor thymidylate synthase, and in vitro antitumor activity.

A convenient synthesis of 5-fluoro-2-thiouracil (11) is based on hydrolytic deamination of 5-fluoro-2-thiocytosine (9). Lewis acid-catalyzed condensation of di-TMS-5-fluoro-2-thiouracil (13) or di-TMS-2-thiouracil (14) with 2-deoxy-3,5-di-O-p-toluyl-D-ribofuranosyl chloride (15) led to mixtures of the beta- and alpha-anomers of 3',5'-toluylated 2'-deoxy-5-fluoro-2-thiouridine (16 and 18) or 2'-deoxy-2-thiouridine (17 and 19), each of which was deblocked with MeOH-NH3 to give the desired free anomeric nucleoside pairs 1, 5 and 3, 7, respectively. These were selectively converted to the corresponding 5'-monophosphates 2, 6 and 4, 8, with the aid of the wheat shoot phosphotransferase system. Conformations of the nucleosides 1, 3, 5, 7 are deduced from 1H NMR spectra, and circular dichroism spectra for nucleotide anomeric pairs 2, 6 and 4, 8 are reported. Whereas beta-2-thio-dUMP (4) was a good substrate (Km approximately 10(-5) M), beta-5-fluoro-2-thio-dUMP (2) proved to be a potent competitive, slow-binding inhibitor (Ki approximately 10(-8) M) of the purified enzymes from Ehrlich ascites carcinoma and L1210 cells. The alpha-anomer 6 was a weak inhibitor, with Ki in the mM range, and its congener 8 hardly interacted with the enzyme. The beta-anomer 1 exhibited antitumor activity in a mouse leukemic cell line L5178Y (IC50 approximately 10(-6) M), hence 40-100-fold weaker than 5-fluoro-dUrd. Its alpha-anomer 5 was 10-fold less active, but exhibited at least 10-fold higher selectivity with respect to the tumor cells than the beta-anomer 1.

At least four regulatory genes control sulphur metabolite repression in Aspergillus nidulans.

Mutations in four genes: sconA (formerly suA25meth, mapA25), sconB (formerly mapB1), sconC and sconD, the last two identified in this work, relieve a group of sulphur amino acid biosynthetic enzymes from methionine-mediated sulphur metabolite repression. Exogenous methionine has no effect on sulphate assimilation in the mutant strains, whereas in the wild type it causes almost complete elimination of sulphate incorporation. In both mutant and wild-type strains methionine is efficiently taken up and metabolized to S-adenosylmethionine, homocysteine and other compounds, scon mutants also show elevated levels of folate-metabolizing enzymes which results from the large pool of homocysteine found in these strains. The folate enzymes appear to be inducible by homocysteine and repressible by methionine (or S-adenosylmethionine).

Ludwik Rajchman--international health leader.

Ludwik Rajchman was a man caught up in the whirlwind of international politics. He suffered from the conquest of his country, Poland, by both Nazism and Communism yet managed to rise to eminence as a leader of the Health Organisation of the League of Nations and then of UNICEF.