Colonoscopy is the preferred colorectal cancer screening method in a population-based program.

BACKGROUND AND STUDY AIMS: Various screening methods for colorectal cancer (CRC) are promoted by professional societies; however, few data are available about the factors that determine patient participation in screening, which is crucial to the success of population-based programs. This study aimed (i) to identify factors that determine acceptance of screening and preference of screening method, and (ii) to evaluate procedure success, detection of colorectal neoplasia, and patient satisfaction with screening colonoscopy. PATIENTS AND METHODS: Following a public awareness campaign, the population aged 50 - 80 years was offered CRC screening in the form of annual fecal occult blood tests, flexible sigmoidoscopy, a combination of both, or colonoscopy. RESULTS: 2731 asymptomatic persons (12.0 % of the target population) registered with and were eligible to take part in the screening program. Access to information and a positive attitude to screening were major determinants of participation. Colonoscopy was the method preferred by 74.8 % of participants. Advanced colorectal neoplasia was present in 8.5 %; its prevalence was higher in males and increased with age. Significant complications occurred in 0.5 % of those undergoing colonoscopy and were associated with polypectomy or sedation. Most patients were satisfied with colonoscopy and over 90 % would choose it again for CRC screening. CONCLUSIONS: In this population-based study, only a small proportion of the target population underwent CRC screening despite an extensive information campaign. Colonoscopy was the preferred method and was safe. The determinants of participation in screening and preference of screening method, together with the distribution of colorectal neoplasia in different demographic categories, provide a rationale for improving screening procedures.

Radioimmunotherapy consolidation and rituximab maintenance in the initial treatment of follicular lymphoma.

ABSTRACT: Several reports have documented similar efficacies and tolerable toxicities of radioimmunotherapy (RIT) consolidation and rituximab maintenance after initial R-chemotherapy of follicular lymphoma. The relative merits of these two interventions are currently under discussion. We now raise the question whether both RIT consolidation and rituximab maintenance should be used together aiming to augment the results achievable with R-chemotherapy.

The brazilian leishmaniasis control program

The control methods used in Brazil for both cutaneous and visceral leishmaniasis by the Ministry of Health's National Health Foundation (Fundação Nacional de Saúde) are presented. Data referring to the programme between 1980 and 1991 is presented. There was an increase in the total number of notified cases of cutaneous leishmaniasis until 1987 and from this date onwards the number has remained between 23,000 and 26,000 per year. There were significantly fewer cases of visceral leishmaniasis during the same period and until 1991 the greatest number of cases reported in one year was 2,511 in 1985. The overall picture is that it is difficult to evaluate to what extent the control methods employed have reduced the number of cases of either form of the disease. It is suggested that there is an urgent need for a closer approximation of research and health workers to review the actual control strategies and to define procedures capable of assessing accurately their impact.

Aggregate cultures of foetal rat liver cells: development and maintenance of liver gene expression.

Rotation-mediated aggregate cultures of foetal rat liver cells were prepared and grown in a chemically defined medium. Their capacity for cellular organisation and maturation was studied over a culture period of 3 wk by using both morphologic and biochemical criteria. It was found that within each aggregate, distinct liver cell types were present and attained their normal, differentiated phenotype. Parenchymal cells formed small acini with a central lumen. Within the first 2 wk in culture, albumin and ferritin mRNA levels were maintained, while the alpha-fetoprotein mRNA levels decreased, and tyrosine aminotransferase (TAT) gene expression increased. No significant response to glucocorticoids was observed in early cultures, whereas after 3 wk a marked increase in TAT mRNA levels was elicited by dexamethasone and glucagon (additive stimulatory effects). The results show that foetal rat liver cells cultured in a chemically defined medium are able to rearrange themselves into histotypic structures, and display a developmental pattern of gene expression comparable to that of perinatal rat liver in vivo. This culture system offers therefore a useful model to study the development and function of liver cells.

Biological control program against simuliids in the State of São Paulo, Brazil

In Brazil, the use of biological vector-control methods has been largely confined to experimental research, with little or no application of such techniques by public institutions responsible for implementing control programs. The notable exceptions have been the black fly control program carried out by the Health Secretariat in the State of São Paulo. Since the 1980s, São Paulo's "Superintendência de Controle de Endemias" has been conducting studies on the viability of using Bacillus thuringiensis (H-14) for simuliid control, and the results have been so encouraging that the agency has now incorporated this method into its Simuliid Control Program.

Schistosomiasis control in China

After three decades' efforts, schistosomiasis japonica were controlled in one-third (4/12) of endemic provinces and 68.2 (259/380) of endemic counties throughout the country. The remaining 121 endemic counties are located primarily in the lake and mountainous regions. The epidemiological and ecological features of the lake and mountainous areas are different from the other endemic areas. The major schistosomiasis control efforts in China can be characterized as follows: (1) Application of centralized leadership and management, since schistosomiasis control is a task not only of the Ministry of Public Health, but also of all local governments in the endemic areas; (2) Integration of actions taken by various departments or bureaus, such as agriculture, water conservation and public health; (3) Promotion of mass participation; (4) Organization of strong professional teams; (5) Raising sufficient funds. Strategies on schistosomiasis control applied in different areas are divided into three levels: (1) In the areas where the schistosomiasis has been successfully controlled, surveillance must be maintained and immediate action should be taken where new infections occur and/or vector snails are found, so that control can be reestablished quickly; (2) In the areas where schistosomiasis has been partially controlled, any residents and/or live-stock infected should be examined and treated promptly with due care, and environment modifying and/or mollusciding must be used to eliminate the remaining snails; (3) In the areas where transmission has not been controlled, the main strategy is to control morbidity. Mass or selective chemotherapy with praziquental should be applied to both infected persosns and the live-stock, and environment modification for the snail-ridden areas should be taken but should be coordinated with agriculture where possible. Advance cases must be treated; and epidemics of Katayama fever prevented; water supply and sanitation shoud be improved and health education emphasized. Annual mass or selective chemotherapy with praziquental both reduces the prevalence rate and decreases the intensity of the infection for inhabitants and live-stock. As a consequence of the therapy a low prevalence rate can be obtained in a short time. The length of such arrangement period can be decided in accordance with the prevalence of the infection before the drug program is begun. Therefore,a maintenance phase is urgently needed. As China's ecomony expands and people's living standard rises, schistosomiasis will be controlled more effectively and successfully.

On the maintenance of sex-chromosome polymorphism by sex-antagonistic selection

Complex sex-determination systems are a priori unstable and require specific selective forces for their maintenance. Analytical derivations have suggested that sex-antagonistic selection may play such a role, but this assumed absence of recombination between the sex-determining and sex-antagonistic genes. Using individual-based simulations, and focusing on the sex chromosome and coloration polymorphisms of platy fishes as a case study, we show that the conditions for polymorphism maintenance induce female-biases in primary sex ratios, so that sex-ratio selection makes the system collapse towards male- or female heterogamety as soon as recombinant genotypes appear. However, a polymorphism can still be maintained under scenarios comprising strong sexual selection against dull males, mild natural selection against bright females, and low recombination rates. Though such conditions are plausibly met in natural populations of fishes harbouring such polymorphisms, quantitative empirical evaluations are required to properly test whether sex-antagonistic selection is a causal agent, or if other selective processes are required (such as local mate competition favouring female biased sex ratios).

Evaluation of the impact of a therapeutic drug monitoring program in a Swiss University Hospital

Background and objective: Therapeutic Drug Monitoring (TDM) has been introduced early 1970 in our hospital (CHUV). It represents nowadays an important routine activity of the Division of Clinical Pharmacology and Toxicology (PCL), and its impact and utility for clinicians required assessment. This study thus evaluated the impact of TDM recommendations in terms of dosage regimen adaptation. Design: A prospective observational study was conducted over 5 weeks. The primary objective was to evaluate the application of our TDM recommendations and to identify potential factors associated to variations in their implementation. The secondary objective was to identify pre-analytical problems linked to the collection and processing of blood samples. Setting: Four representative clinical units at CHUV. Main outcome measure: Clinical data, drug related data (intake, collection and processing) and all information regarding the implementation of clinical recommendations were collected and analyzed by descriptive statistics. Results: A total of 241 blood measurement requests were collected, among which 105 triggered a recommendation. 37% of the recommendations delivered were applied, 25 % partially applied and 34% not applied. In 4% it was not applicable. The factors determinant for implementation were the clinical unit and the mode of transmission of the recommendation (written vs oral). No clear difference between types of drugs could be detected. Pre-analytical problems were not uncommon, mostly related to completion of request forms and delays in blood sampling (equilibration or steady-state not reached). We have identified 6% of inappropriate and unusable drug level measurements that could cause a substantial cost for the hospital. Conclusion: This survey highlighted a better implementation of TDM recommendations in clinical units where this routine is well integrated and understood by the medical staff. Our results emphasize the importance of communication with the nurse or the physician in charge, either to transmit clinical recommendations or to establish consensual therapeutic targets in specific conditions. Development of strong partnerships between clinical pharmacists or pharmacologists and clinical units would be beneficial to improve the impact of this clinical activity.

Best practice in the management of mild-to-moderately active ulcerative colitis and achieving maintenance of remission using mesalazine.

Optimizing treatment goals in ulcerative colitis requires recognizing the needs of patients. It is increasingly recognized that adapting treatment strategies aligned with patient needs can improve patient compliance and consequently minimize relapse rates. Tailoring of treatment strategies can improve not only patient quality of life, and decrease the number harmed by adverse events from more potent drugs, but can also save valuable healthcare costs by avoiding high-cost treatment interventions associated with acute ulcerative colitis. This review will consider several elements of mesalazine management from the patient perspective based on a range of clinical and patient-focused evidence. By highlighting patient preferences in disease management it is envisaged that this review will aid physicians to optimize treatment decisions with the different mesalazine preparations available.

Vedolizumab as induction and maintenance therapy for Crohn's disease.

BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

Maintenance of hepatic nuclear factor 6 in postnatal islets impairs terminal differentiation and function of beta-cells.

The Onecut homeodomain transcription factor hepatic nuclear factor 6 (Hnf6) is necessary for proper development of islet beta-cells. Hnf6 is initially expressed throughout the pancreatic epithelium but is downregulated in endocrine cells at late gestation and is not expressed in postnatal islets. Transgenic mice in which Hnf6 expression is maintained in postnatal islets (pdx1(PB)Hnf6) show overt diabetes and impaired glucose-stimulated insulin secretion (GSIS) at weaning. We now define the mechanism whereby maintenance of Hnf6 expression postnatally leads to beta-cell dysfunction. We provide evidence that continued expression of Hnf6 impairs GSIS by altering insulin granule biosynthesis, resulting in a reduced response to secretagogues. Sustained expression of Hnf6 also results in downregulation of the beta-cell-specific transcription factor MafA and a decrease in total pancreatic insulin. These results suggest that downregulation of Hnf6 expression in beta-cells during development is essential to achieve a mature, glucose-responsive beta-cell.

Characterization of subpopulations (clones and subclones) of the 21 SF strain of Trypanosoma cruzi after long lasting maintenance in the laboratory

Several studies have shown a clonal structure of Trypanosoma cruzi and its possible correlation with the behavioral heterogeneity of the parasite strains. In the present study, the 21 SF strain, that have been maintained in laboratory by successive passages in mice, for more than 15 years, showing a stability of biological and isoenzymic characteristics has been cloned, with the objective of establishing the characters of its clones and subclones. With the technique of isolation of a single parasite from the blood of infected mice, 5 clones and 14 subclones have been obtained. After four passages into mice, inoculum of 10(5) was obtained for each clone and subclone and inoculated into mice weighing 10 to 12 g. These were used for the study of the biological behavior of the clones: evolution of parasitemia, morphology of blood forms and host mortality. For isoenzymic characterization, the clones and subclones were analyzed for ALAT, ASAT, GPI and PGM enzymes. Results have shown that the 5 clones and the 14 subclones disclosed a biological behavior similar to the parental strain, with minor variability of the parasitemic profiles and also the same isoenzymic patterns. These results confirm the stability of the 21 SF strain and indicate a clonal homogeneity of its populations. This is compatible with the hypothesis that the T. cruzi strains represent an equilibrium of either homogenous or heterogeneous populations.

Update of the Gene Discovery Program in Schistosoma mansoni with the Expressed Sequence Tag Approach

Continuing the Schistosoma mansoni Genome Project 363 new templates were sequenced generating 205 more ESTs corresponding to 91 genes. Seventy four of these genes (81%) had not previously been described in S. mansoni. Among the newly discovered genes there are several of significant biological interest such as synaptophysin, NIFs-like and rho-GDP dissociation inhibitor

Evolution, maintenance and ecological consequences of genetic caste determination in " Pogonomyrmex " harvester ants

Summary Division of labor between reproducers (queens) and helpers (workers) is the main characteristic of social insect societies and at the root of their ecological success. Kin selection models predict that phenotypic differences between queens and workers should result from environmental rather than from genetic differences. However, genetic effects on queen and worker differentiation were found in two populations-of Pogonomyrmex harvester ants. Each of the two populations is composed of two genetically distinct lineages. Queens (which can be of either lineage) generally mate with males of their own and of the alternate lineage and produce two types of female offspring, those fertilized by males of the queens' lineage which develop into queens and those fertilized by males of the alternate lineage which develop into workers. All four lineages were further suggested to be themselves of hybrid origin between-the species P: barbatus and P. rugosus, in which queens and workers do not differ genetically. In a first set of experiments, we tested if female caste determination (the differentiation into queens and workers) in the lineages was genetically hardwired and if it was associated with costs in terms of the ability to optimally allocate resources to the production of queens and workers. To this end we first mated queens of-two lineages to a single male. Queens mated to a male of the alternate lineage successfully raised worker offspring whereas queens mated to a male of their own lineage almost always failed to produce workers. This reveals that pure-lineage individuals have lost the ability to develop into workers. Second, we analyzed offspring produced by naturally mated queens. During the stage of colony founding when only workers are produced, naturally mated queens laid a high proportion of pure-lineage eggs but the large majority of these eggs failed to develop. As a consequence, the number of offspring produced by incipient colonies decreased linearly with the proportion of pure-lineage eggs laid by queens. Moreover, queens of the lineage most commonly represented in a given population produced more pure-lineage eggs, in line with the view that they mate randomly with the two types of males and indiscriminately use their sperm. Altogether these results predict frequency-dependent founding success for pairs of lineages because queens of the more common lineage will produce more pure-lineage eggs and their colonies be less successful during the stage of colony founding. To describe the distribution of populations characterized with genetic caste determination relative to the populations with environmental caste determination we genotyped queens and workers collected during a large survey of -additional populations. Genetic caste determination associated with pairs of interbreeding lineages was frequent and widespread in the studied range and we identified four additional lineages displaying genetic caste determination. Overall, there were thus eight highly differentiated lineages with genetic caste determination. These lineages always co-occurred in the same complementary lineage pairs. Three of the four lineage pairs appeared to have a common origin, while their relationship with the forth could not be resolved. The genetic survey also revealed that, in addition to being genetically isolated from one another, all eight lineages were genetically distinct from P. rugosus and P. barbatus, even when colonies of interbreeding lineages co-occurred with colonies of either putative parent at the same site. This raised the question of the mechanisms involved in the reproductive isolation between the lineages and the parental species and between the two lineages of a lineage pair. At a site where one lineage pair co-occurred with P. rugosus, we identified two pre-zygotic mechanisms (differences in timing for mating flights between P. rugosus and the lineage pair and assortative mating) and one post-zygotic mechanism (high levels of hybrid unviablility) which in combination may largely account for the reproductive isolation between the lineages and their parental species. The mechanisms accounting for the reproductive isolation between the two lineages of a lineage pair varied across lineage pairs. In one lineage pair, inter-lineage individuals exclusively occurred in the sterile worker caste, raising the possibility that inter-lineage eggs have completely lost the ability to develop into queens in this lineage pair and that there is thus no opportunity for gene flow. In each of the three remaining lineage pairs, inter-lineage queens were produced by a minority of colonies. In these lineage pairs, colonies headed by inter-lineage queens failed to grow sufficiently to produce reproductive individuals which may account for the reproductive isolation between co-occurring lineages in three lineage pairs. In conclusion, the results of this thesis show that genetic caste determination is costly but widespread in Pogonomyrmex harvester ants. Reproductive isolation among the lineages and between the lineages and the parental species as well as frequency-dependent founding success for co-occurring lineages may contribute to the persistence of this extraordinary system. Résumé La division du travail entre individus reproducteurs (les reines) et individus non-reproducteurs (ouvrières) représente la caractéristique principale des sociétés d'insectes et est à la base de leur succès écologique. Des modèles de sélection de parentèle prédisent que les différences phénotypiques entre reines et ouvrières devraient provenir d'effets environnementaux plutôt que de différences génétiques. Malgré ce fait, des effets génétiques sur la différentiation entre reines et ouvrières ont été montrés dans deux populations de fourmis moissonneuses du genre Pogonomyrmex. Chacune des deux populations est composée de deux lignées génétiquement distinctes. Les reines de chaque lignée s'accouplent en général avec des mâles de leur propre lignée ainsi qu'avec des mâles de l'autre lignée et produisent deux types d'oeufs, ceux qui sont fécondés par les mâles de leur propre lignée qui se développent en nouvelles reines et ceux qui sont fécondés par les mâles de l'autre lignée qui se développent en ouvrières. Il a été suggéré que les lignées sont elles-mêmes des hybrides entre les deux espèces P. barbatus et P. rugosus. Dans ces deux espèces, les reines et ouvrières ne sont pas génétiquement distinctes. Dans une première série d'expériences, nous avons testé si la détermination de la caste femelle (le développement en reine ou en ouvrière) est génétiquement rigide et si elle est associée à des coûts en terme de capacité à allouer de façon optimale les ressources pour la production de reines et d'ouvrières. Pour cela nous avons accouplé des reines de deux lignées avec un seul mâle. Les reines accouplées avec un mâle de l'autre lignée ont élevé de nouvelles ouvrières avec succès alors que les reines accouplées avec un mâle de leur propre lignée ont presque toujours échoué à produire des ouvrières. Ceci montre que les individus de lignée pure ont perdu la capacité de se développer en ouvrière. Deuxièmement, nous avons analysé la descendance de reines qui se sont accouplées naturellement. Durant le stade de fondation de la colonie, où seules des ouvrières sont élevées, les reines accouplées naturellement ont pondu une grande proportion d'oeufs de lignée pure mais la majorité de ces derniers ne se sont pas développés. En conséquence, le nombre de descendants produits par des colonies fondatrices diminuait linéairement avec la proportion des oeufs de lignée pure pondus par la reine en accord avec l'hypothèse que les reines s'accouplent au hasard avec les deux types de mâles et utilisent leur sperme aléatoirement. Dans l'ensemble; ces résultats prédisent un succès de fondation fréquence-dépendant pour les deux lignées, car les reines de la lignée la plus fréquente produiront .plus d'oeufs de lignée pure et leurs colonies auront moins de succès lors de la fondation de colonies par rapport aux colonies de la lignée la moins fréquente. Pour décrire la distribution des-populations caractérisées par une détermination génétique des castes par rapport aux populations caractérisées par une détermination environnementale des castes, nous avons génotypé des reines et des ouvrières qui ont été collectées lors d'une analyse de populations supplémentaires. La détermination génétique des castes associée à des croisements entre lignées est fréquente et largement répartie dans l'aire étudiée. Nous avons identifié quatre lignées supplémentaires, ayant une détermination génétique des castes, pour un total de huit lignées. Ces huit lignées forment quatre paires de lignées et on ne trouve jamais deux lignées de paires différentes, dans une population. Trois des quatre paires de lignées s'avèrent avoir une origine commune alors que leur relation avec la quatrième paire de lignées n'a pas pu être résolue. L'analyse génétique de populations supplémentaires a également révélé qu'en plus d'être génétiquement isolées les unes des autres, les huit lignées sont génétiquement distinctes de P. rugosus et P. barbatus même si les colonies d'une paire de lignées se trouvent en sympatrie avec l'une ou l'autre des espèces parentales. Ceci relève la question des mécanismes impliqués dans l'isolation reproductive entre les lignées et les espèces parentales ainsi qu'entre les deux lignées d'une paire. En étudiant un site où une paire de lignées se trouve en sympatrie avec P. rugosus, nous avons identifié deux mécanismes pré-zygotiques (des différences dans le timing du vol nuptial entre P. rugosus et les lignées et des accouplements assortis) ainsi qu'un mécanisme post-zygotique (un niveau élevé de non-viabilité des hybrides). En combinaison, ces mécanismes peuvent largement expliquer l'isolement reproductif entre les lignées et leurs espèces parentales. Les mécanismes contribuant à l'isolement reproductif entre les deux lignées d'une paire variaient entre paires de lignées. Dans une paire, les individus de génotype inter-lignée se trouvent uniquement dans la caste stérile des ouvrières, suggérant qu'il n'y a pas d'opportunité pour avoir du flux de gènes entre les deux lignées ce cette paire. Dans chacune des trois autres paires de lignées des nouvelles reines de génotype inter-lignée sont produites par une minorité de colonies. Par contre, les colonies avec une reine mère de génotype inter-lignée ne se développent pas suffisamment pour produire des individus reproducteurs. Ceci peut donc expliquer pourquoi il n'y a pas de flux de gènes entre les deux lignées de trois paires. En conclusion, les résultats de cette thèse montrent que la détermination génétique de la caste est coûteuse mais très répandue chez les fourmis. moissonneuses du genre Pogonomyrmex. L'isolement reproductif des lignées entre elles et avec les espèces parentales, ainsi qu'un succès de fondation fréquence-dépendant contribuent à la persistance de ce système extraordinaire.