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Background Tackling neonatal mortality is essential for the achievement of the child survival millennium development goal. There are just under 4 million neonatal deaths, accounting for 38% of the 10.8 million deaths among children younger than 5 years of age taking place each year; 99% of these occur in low- and middle-income countries where a large proportion of births take place at home, and where postnatal care for mothers and neonates is either not available or is of poor quality. WHO and UNICEF have issued a joint statement calling for governments to implement "Home visits for the newborn child: a strategy to improve survival", following several studies in South Asia which achieved substantial reductions in neonatal mortality through community-based approaches. However, their feasibility and effectiveness have not yet been evaluated in Africa. The Newhints study aims to do this in Ghana and to develop a feasible and sustainable community-based approach to improve newborn care practices, and by so doing improve neonatal survival. Methods Newhints is an integrated intervention package based on extensive formative research, and developed in close collaboration with seven District Health Management Teams (DHMTs) in Brong Ahafo Region. The core component is training the existing community based surveillance volunteers (CBSVs) to identify pregnant women and to conduct two home visits during pregnancy and three in the first week of life to address essential care practices, and to assess and refer very low birth weight and sick babies. CBSVs are supported by a set of materials, regular supervisory visits, incentives, sensitisation activities with TBAs, health facility staff and communities, and providing training for essential newborn care in health facilities. Newhints is being evaluated through a cluster randomised controlled trial, and intention to treat analyses. The clusters are 98 supervisory zones; 49 have been randomised for implementation of the Newhints intervention, with the other 49 acting as controls. Data on neonatal mortality and care practices will be collected from approximately 15,000 babies through surveillance of women of child-bearing age in the 7 districts. Detailed process, cost and cost-effectiveness evaluations are also being carried out. Trial registration http://www.clinicaltrials.gov (identifier NCT00623337)

Summary Background A previous trial in Nepal showed that supplementation with vitamin A or its precursor (betacarotene) in women of reproductive age reduced pregnancy-related mortality by 44% (95% CI 16–63). We assessed the effect of vitamin A supplementation in women in Ghana. Methods ObaapaVitA was a cluster-randomised, double-blind, placebo-controlled trial undertaken in seven districts in Brong Ahafo Region in Ghana. The trial area was divided into 1086 small geographical clusters of compounds with fieldwork areas consisting of four contiguous clusters. All women of reproductive age (15–45 years) who gave informed consent and who planned to remain in the area for at least 3 months were recruited. Participants were randomly assigned by cluster of residence to receive a vitamin A supplement (25 000 IU retinol equivalents) or placebo capsule orally once every week. Randomisation was blocked and based on an independent, computer-generated list of numbers, with two clusters in each fieldwork area allocated to vitamin A supplementation and two to placebo. Capsules were distributed during home visits undertaken every 4 weeks, when data were gathered on pregnancies, births, and deaths. Primary outcomes were pregnancy-related mortality and all-cause female mortality. Cause of death was established by verbal post mortems. Analysis was by intention to treat (ITT) with random-effects regression to account for the cluster-randomised design. Adverse events were synonymous with the trial outcomes. This trial is registered with ClinicalTrials.gov, number NCT00211341. Findings 544 clusters (104 484 women) were randomly assigned to vitamin A supplementation and 542 clusters (103 297 women) were assigned to placebo. The main reason for participant drop out was migration out of the study area. In the ITT analysis, there were 39 601 pregnancies and 138 pregnancy-related deaths in the vitamin A supplementation group (348 deaths per 100 000 pregnancies) compared with 39 234 pregnancies and 148 pregnancy-related deaths in the placebo group (377 per 100 000 pregnancies); adjusted odds ratio 0·92, 95% CI 0·73–1·17; p=0·51. 1326 women died in 292 560 woman-years in the vitamin A supplementation group (453 deaths per 100 000 years) compared with 1298 deaths in 289 310 woman-years in the placebo group (449 per 100 000 years); adjusted rate ratio 1·01, 0·93–1·09; p=0·85. Interpretation The body of evidence, although limited, does not support inclusion of vitamin A supplementation for women in either safe motherhood or child survival strategies. Funding UK Department for International Development, and USAID.

Schwann cells are the myelinating glia cells of the peripheral nervous system (PNS). In inflammatory neuropathies like the Guillain-Barr syndrome (GBS) Schwann cells become target of an autoimmune response, but may also modulate local inflammation. Here, we tested the functional relevance of Schwann cell derived MHC expression in an in vitro coculture system. Mouse Schwann cells activated proliferation of ovalbumin specific CD8+ T cells when ovalbumin protein or MHC class I restricted ovalbumin peptide (Ova(257-264) SIINFEKL) was added and after transfection with an ovalbumin coding vector. Schwann cells activated proliferation of ovalbumin specific CD4+ T cells in the presence of MHC class 11 restricted ovalbumin peptide (Ova(323-339) ISQAVHAAHAEINEAGR). CD4+ T-cell proliferation was not activated by ovalbumin protein or transfection with an ovalbumin coding vector. This indicates that Schwann cells express functionally active MHC class I and II molecules. In this study, however, Schwann cells lacked the ability to process exogenous antigen or cross-present endogenous antigen into the MHC class 11 presentation pathway. Thus, antigen presentation may be a pathological function of Schwann cells exacerbating nerve damage in inflammatory neuropathies. (C) 2009 Elsevier Inc. All rights reserved

Formative research is often used to inform intervention design, but the design process is rarely reported. This study describes how an integrated home visit intervention for newborns in Ghana was designed. As a first step in the design process, the known intervention parameters were listed, information required to refine the intervention was then identified and a formative research strategy designed. The strategy included synthesizing available data, collecting data on newborn care practices in homes and facilities, on barriers and facilitators to adopting desired behaviors and on practical issues such as whom to include in the intervention. The data were used to develop an intervention plan through workshops with national and international stakeholders and experts. The intervention plan was operationalized by district level committees. This included developing work plans, a creative brief for the materials and completing a community volunteer inventory. The intervention was then piloted and the intervention materials were finalized. The design process took over a year and was iterative. Throughout the process, literature was reviewed to identify the best practice. The intervention focuses on birth preparedness, using treated bednets in pregnancy, early and exclusive breastfeeding, thermal care, special care for small babies and prompt care seeking for newborns with danger signs. The need for a problem-solving approach was identified to help ensure behavior change. A subset of behaviors were already being performed adequately, or were the focus of other interventions, but were important to reinforce in the visits. These include attending antenatal care and care seeking for danger signs in pregnancy. On the basis of the intervention content, the timing of newborn deaths and the acceptability of visits, two antenatal and three visits in the first week of life (days 1, 3 and 7) were planned. Several household members were identified to include in the visits as they were involved in newborn care or they made financial decisions. Birth attendants and health workers were often the locus of control for immediate newborn care, and sensitization activities were designed to improve their practices and to help ensure that families received consistent messages. An existing cadre of community volunteers was identified to deliver the intervention-these volunteers were already trusted and accepted by the community, already visited pregnant women at home and had the time and commitment to deliver the intervention. A supervision and remuneration system was developed through discussions with the volunteers and at the planning workshops. The need for community entry activities was identified to garner community support for the intervention, to encourage self-identification of pregnant and delivered women and to motivate the volunteer through community recognition. Formative research is an essential step in helping to ensure the development of an effective, appropriate and sustainable intervention.

Numerous mouse myelin mutants are available to analyze the biology of the peripheral nervous system related to health and disease in vivo. However, robust in vitro biochemical characterizations of players in peripheral nerve processes are still not possible due to the limited growth capacities of Schwann cells. In order to generate cell lines from peripheral nerves that are amenable to experimental manipulation, we have isolated Schwann cells from transgenic mice (H-2Kb-tsA58) carrying the temperature sensitive SV40 large T oncogene under the control of the interferon gamma (IFNgamma) H-2Kb promoter. These cells are immortalized at 33 degrees C when the SV40 large T antigen has a stable conformation. At the non-permissive temperature of 37 degrees C and in the absence of IFNgamma, the growth rate of the cultures reduces and typical Schwann cell markers such as p75(NGFR) become upregulated. The conditionally immortalized Schwann cells allow genetic manipulation as demonstrated here by the generation of a stable eGFP expressing cell line. They regain their characteristic non-immortalized properties at non-permissive temperature and differentiate to myelin-forming cells when seeded on dorsal root ganglia neurons. The Schwann cell lines derived are valuable tools for in vitro studies involving demyelinating diseases.

OBJECTIVES: To assess the reliability and validity of a translated version of the American Hospital-level Consumer Assessment of Health Plans Survey (H-CAHPS) instrument for use in Dutch health care. DATA SOURCES/STUDY SETTING: Primary survey data from adults aged 18 years or more who were recently discharged from two multispecialty city hospitals in the Netherlands. STUDY DESIGN: We used forward and backward translation procedures and a panel of experts to adapt the 66-item pilot H-CAHPS into a 70-item Dutch instrument. Descriptive statistics and standard psychometric methods were then used to test the reliability and validity of the new instrument. DATA COLLECTION: From late November 2003 to early January 2004, the survey was administered by mail to 1,996 patients discharged within the previous 2 months. PRINCIPAL FINDINGS: Analyses supported the reliability and validity of the following 7-factor H-CAHPS structure for use in Dutch hospitals: on doctor's communication, nurses' communication, discharge information, communication about medication, pain control, physical environment of hospital, and nursing services. The internal consistency reliability of the scales ranged from 0.60 to 0.88. Items related to "family receiving help when on visit,""hospital staff introducing self," and "admission delays" did not improve the psychometric properties of the new instrument. CONCLUSIONS: These findings suggest that the H-CAHPS instrument is reliable and valid for use in the Dutch context. However, more research will be needed to support its equivalence to the United States version, and its use for between-hospital comparisons.

Contains fulltext : 53382.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To identify and weigh the various criteria for priority setting, and to assess whether a recently evaluated lung health programme in Nepal should be considered a priority in that country. METHODS: Through a discrete choice experiment with 66 respondents in Nepal, the relative importance of several criteria for priority setting was determined. Subsequently, a set of interventions, including the lung health programme, was rank ordered on the basis of their overall performance on those criteria. RESULTS: Priority interventions are those that target severe diseases, many beneficiaries and people of middle-age, have large individual health benefits, lead to poverty reduction and are very cost-effective. Certain interventions in tuberculosis control rank highest. The lung health programme ranks 13th out of 34 interventions. CONCLUSION: This explorative analysis suggests that the lung health programme is among the priorities in Nepal when taking into account a range of relevant criteria for priority setting. The multi-criteria approach can be an important step forward to rational priority setting in developing countries.

An appropriate quality of medical care including dental care should be an objective of every government that aims to improve the oral health of its population.To determine performance indicators that could be used to assess the quality of primary dental care at different levels of a health care system, the sources for data collection and finally, the dimensions of quality measured by these indicators.An explorative study of the international literature was conducted using medical databases, journals and books, and official websites of organisations and associations.This resulted in a set of 57 indicators, which were classified into the following dimensions for each intended user group: For patients: health outcomes and subjective indicators; for professionals: their performance and the rates of success, failure and complications; for health care system managers and policymakers: their resources, finances and health care utilisation.A set of 57 performance indicators were identified to assess the quality of primary dental care at the levels of patients, professionals and the health care system. These indicators could be used by managers and decision-makers at any level of the health care system according to the characteristics of the services.

Objectives: To identify and weigh the various criteria for priority setting, and to assess whether a recently evaluated lung health programme in Nepal should be considered a priority in that country. Methods: Through a discrete choice experiment with 66 respondents in Nepal, the relative importance of several criteria for priority setting was determined. Subsequently, a set of interventions, including the lung health programme, was rank ordered on the basis of their overall performance on those criteria. Results: Priority interventions are those that target severe diseases, many beneficiaries, and people of middle-age, have large individual health benefits, lead to poverty reduction, and are very cost-effective. Certain interventions in TB control rank highest. The lung health programme ranks 13th out of 34 interventions. Conclusion: This explorative analysis suggests that the lung health programme is among the priorities in Nepal when taking into account a range of relevant criteria for priority setting. The multi-criteria approach can be an important step forward to rational priority setting in developing countries.

Background The fact that tuberculosis can be treated with the DOTS strategy (Directly Observed Treatment, Short-course) is not enough to control the disease. Patients have to find their way to tuberculosis treatment first. To better understand the route to tuberculosis treatment in rural Nepal we interviewed twenty-six patients under treatment. Methods In semi-structured interviews patients shared their disease history and health seeking behaviour. The analysis focused on the encounters with the health care system before enrolment in the tuberculosis treatment program. Results Patient routes often started in the medical shop and led via intricate routes with multiple providers to facilities with higher qualified and more competent staff where tuberculosis was diagnosed. Several factors influenced the route to tuberculosis treatment. Besides known patients factors (such as severity of complaints, the ability to pay for services, availability of services and peer support for choosing a provider) specific health services factors were also identified. These included the perceived quality, costs and service level of a provider, and lack of provider initiated referral. Self referral because of waned trust in the provider was very common. In contrast, once tuberculosis was considered a possible diagnosis, referral to diagnostic testing and tuberculosis treatment was prompt. Conclusion Patient routes towards tuberculosis treatment are characterised by self referral and include both private and public health care providers. Once tuberculosis is suspected referral for diagnosis and treatment is prompt. Given the importance of the private practitioners in the patient routes, quality improvement initiatives need to address not only the public sector but the private health care sector as well.

Background: In the Dutch social insurance system, based on regulated competition, sickness funds should attract clients by contracting efficient and qualitatively good services. For that sake, sickness funds need information about their own performance and about the quality of care they contract, as perceived by their insured. In the Unites States, the Consumer Assessment of Health Plan Surveys (CAHPS) have been developed specifically for that purpose. CAHPS instruments focus on the patient-centeredness of health care (e.g. respect, dignity, prompt attention) and the service of the health plan. These surveys have recently been adopted by the largest Dutch sickness fund (AGIS). Aim: This paper presents the results of a validation study, commissioned by AGIS Zorgverzekeringen, looking at: a) Can the CAHPS be adapted for use in the context of the Dutch social insurance system? b) Do these questionnaires generate valid information about the quality of health care and the performance of Dutch sickness funds? Methods: The American core CAHPS was translated forward and backward. It was subsequently piloted in a sample of 977 AGIS clients (response rate 56%, with a slight over-representation of elderly). Internal validation consisted of evaluations of item response rates, distributions of scores, reliability analyses, and tests of internal consistency. For external validation data are compared with the American CAHPS benchmark data, and with results of other Dutch studies. Results: In general, the questionnaires are filled out completely and consistently. As expected, the distribution of scores on the perceived quality of care is somewhat skewed towards positive answers. The questionnaire contains a reliable scale about the patient-centerednesscenteredness of care (Cronbach’s alpha .83). That scale correlates significantly with respondents’ general rating of the quality of health care on scale of 0 to 10. The comparison with the American CAHPS benchmark data showed that respondents in the US’ system experience more problems with the accessibility of care than do their Dutch counterparts. However, once patients manage to get into the system, the patient-centeredness of the two health care systems is remarkably similar. Conclusions: It is possible to import American patient questionnaires into the Dutch social insurance system and use them to improve the accountability of sickness funds. Particularly, questions that refer to the primary process in health care (the doctor-patient interaction) generate scores that are quite comparable between the American and the Dutch health system.

High-throughput gene expression analyses of murine models of the peripheral nervous system (PNS), and its cellular components, have yielded enormous amounts of expression data of the PNS in various conditions. These data provided clues for future research directions to further decipher this complex organ in relation to acquired and inherited PNS diseases. Various studies addressing the validity of mouse models for human conditions in other tissues and cell types have indicated that in many cases the mouse model only poorly represents the human situation. To determine how well the mouse can serve as model to study the biological processes occurring in the PNS, we compared the gene expression profiles that we generated for mouse and human sciatic nerve and cultured Schwann cells derived thereof. A two-way analysis based on the differentially expressed genes between the sciatic nerve and the cultured Schwann cell, and which takes into account the differential expression between mouse and man, indicates that the human PNS is well represented by that of the mouse in terms of the "biological processes" ontology.

Nepal. To assess the impact of community mobilization and health worker training on tuberculosis (TB) health services utilization. Questionnaire. The Japan International Cooperation Agency and the Nepal Ministry of Health launched a set of interventions to increase awareness and availability of treatment at government facilities. In 2001 and 2003, a questionnaire was administered to TB patients. In 2001-2002, 77.3% of women and 80.0% of men with TB symptoms consulted at government facilities, compared to 30% of men and 32% of women in 1997-1999. In the absence of any secular causes, this change can be attributed to the increasing community awareness of availability and quality of DOTS

For a planetary base, a reliable life support system including food and water supply, gas generation and waste management is a condition sine qua non. While for a short-term period the life support system may be an open loop, i.e. water, gases and food provided from the Earth, for long-term missions the system has to become more and more regenerative. Advanced life support systems with biological regenerative processes have been studied for many years and the processes within the different compartments are rather complete and known to a certain extent. The knowledge of the associated interfaces, the management of the input and output phases: liquid, solid, gas, between compartments, has been limited. Nowadays, it is well accepted that the management of these phases induces generic problems like capture, separation, transfer, mixing, and buffering. A first ESA study on these subjects started mid 2003. This study, performed by Stork, TNO, Stirling and the University of Guelph, is limited to the main gas components, oxygen, water vapour and carbon dioxide. Ammonia was included as a contaminant component. The study has been started with the establishment of a simulation model (closed loop) to identify the critical items, which is followed by the selection of the gas capture and recovery technologies, the development of a breadboard model and is finished by a set of experiments. For the control of carbon dioxide (CO2), a dedicated activated carbon will be applied. This material, produced by Norit, is applied to control the CO2 at fruit storage, and pressure swing adsorption is applied for regeneration. In the breadboard set-up, electrical swing adsorption will be applied. This rather new technique has been selected to enable the development of a compact system which can be operated within almost any range atmospheric pressure, resulting in a safe system having a low mass. This paper will report the status of these activities. Copyright © 2005 SAE International.

Clinical practice guidelines are used widely to improve the quality of primary health care in different health systems, including those of low-income countries. Often developed at international level and adapted to national contexts to increase the feasibility of effective uptake, guideline initiatives aim to transfer global scientific knowledge into local practice. The WHO's Practical Approach to Lung Health (PAL) is an example of such an initiative and is currently being developed to improve the quality of care for youths and adults with respiratory diseases. We assessed ex-ante the feasibility of successful implementation of PAL in a pilot programme in rural Nepal, studying three components: the quality of the innovation (i.e. the guidelines), the effectiveness of the implementation strategy (i.e. training) and the receptiveness of the social system of health staff at all levels (i.e. social and organizational characteristics). We assessed the guideline innovation with the AGREE instrument for guidelines, the intended implementation strategy by critical comparison with literature on effective strategies, and the social system with both a stakeholder analysis and a descriptive analysis of the health care system at district level. This ex-ante assessment of an adaptive local implementation of international WHO guidelines showed that in July 2002 the 'implementability' of the package was challenged on the three components studied. To increase the chances of successful implementation, the national guideline development process should be improved and the implementation strategy needs to be upgraded. In order to successfully transfer global knowledge into local practice, we need to develop additional multifactorial sustained interventions that tackle other culture-specific and health system-specific barriers as well. The primary health workers are key informants for these barriers.

The salts of amino-acids in an aqueous solution are an excellent alternative to amines for CO2-capture from flue gases. Some of them show excellent oxygen resistance, lower binding energy, and fast reaction kinetics. Two options towards improved and lower cost CO2-capture processes are currently underway: one based on the use of membrane contactors where scale-up is a major issue and one based on precipitating solvents, where the process development is a major focal point. The chapter shows that these options allow the driving force to be maintained at increased loading. The increased loading also leads to low energy consumption for solvent regeneration. To achieve this, however, the heat exchanger needs to be integrated into the regenerator. Results of a preliminary economic evaluation are presented. It is shown that this new technology has the potential to half the investment costs and half the energy consumption for regeneration. The excellent perspective has resulted in further fundamental research to provide a firm basis for the novel capture process based on precipitating solvents. © 2005 Elsevier Ltd. All rights reserved.

Issues. Countries and international organizations have recently renewed their interest in how health systems perform. This has led to the development of performance indicators for monitoring, assessing, and managing health systems to achieve effectiveness, equity, efficiency, and quality. Although the indicators populate conceptual frameworks, it is often not very clear just what the underlying concepts might be or how effectiveness is conceptualized and measured. Furthermore, there is a gap in the knowledge of how the resultant performance data are used to stimulate improvement and to ensure health care quality. Addressing the issues. This paper therefore explores, individually, the conceptual bases, effectiveness and its indicators, as well as the quality improvement dynamics of the performance frameworks of the UK, Canada, Australia, US, World Health Organization, and Organisation for Economic Co-operation and Development. Results. We see that they all conceive health and health system performance in one or more supportive frameworks, but differ in concepts and operations. Effectiveness often implies, nationally, the achievement of high quality outcomes of care, or internationally, the efficient achievement of system objectives, or both. Its indicators are therefore mainly outcome and, less so, process measures. The frameworks are linked to a combination of tools and initiatives to stimulate and manage performance and quality improvement. Conclusions. These dynamics may ensure the proper environment for these conceptual frameworks where, alongside objectives such as equity and efficiency, effectiveness (therefore, quality) becomes the core of health systems performance

Locked nucleic acids (LNA) are novel high-affinity DNA analogs that can be used as genotype-specific drugs. The LNA oligonucleotides (LNA PO ODNs) are very stable in vitro and in vivo without the need for a phosphorothiolated backbone. In this study we tested the biological fate and the efficacy in tumor growth inhibition of antisense oligonucleotides directed against the gene of the large subunit of RNA polymerase II (POLR2A) that are completely synthesized as LNA containing diester backbones. These full LNA oligonucleotides strongly reduce POLR2A protein levels. Full LNA PO ODNs appeared to be very stable compounds when injected into the circulation of mice. Full LNA PO ODNs were continuously administered for 14 days to tumor-bearing nude mice. Tumor growth was inhibited sequence specifically at dosages from 1 mg/kg/day. LNA PO ODNs appeared to be non-toxic at dosages

Loss of heterozygosity (LOH) reduces genes to hemizygosity in cancer cells and presents an absolute difference between normal and cancer cells. The regions of LOH are usually much larger than the tumor suppressor gene, which is lost, and are expected to contain genes that are essential for cell survival. Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man, often giving rise to two or more allelic forms of most genes. SNPs of essential genes that are frequently affected by LOH can be used as a target for a novel therapy against cancer cells with LOH. The SNPs can be targeted by antisense oligonucleotides (ODNs) that will discriminate between two alleles. We have designed allele-specific phosphorothioate ODNs against the gene of the large subunit of RNA polymerase II (POLR2A), a gene located in close proximity to the tumor suppressor gene p53, which frequently shows LOH in cancer cells. This report shows that phosphorothioate antisense ODNs directed against POLR2A can inhibit tumor growth in vivo as efficiently as a well-described antitumor antisense ODN directed against Ha-ras. In addition, we show that a single bp mismatch can be sufficient to obtain allele-specific inhibition of tumor growth, demonstrating that the effects observed are true antisense effects.

We have analyzed the response of a number of human cell lines to treatment with antisense oligodeoxynucleotides (ODNs) directed against RNA polymerase II, replication protein A, and Ha-ras. ODN-delivery to the cells was liposome-mediated or via electroporation, which resulted in different intracellular locations of the ODNs. The ODN-mediated target mRNA reduction varied considerably between the cell lines. In view of the essential role of RNase H activity in this response, RNase H was analyzed. The mRNA levels of RNase H1 and RNase H2 varied considerably in the cell lines examined in this study. The intracellular localization of the enzymes, assayed by green-fluorescent protein fusions, showed that RNase H1 was present throughout the whole cell for all cell types analyzed, whereas RNase H2 was restricted to the nucleus in all cells except the prostate cancer line 15PC3 that expressed the protein throughout the cell. Whole cell extracts of the cell lines yielded similar RNase H cleavage activity in an in vitro liquid assay, in contrast to the efficacy of the ODNs in vivo. Overexpression of RNase H2 did not affect the response to ODNs in vivo. Our data imply that in vivo RNase H activity is not only due to the activity assayed in vitro, but also to an intrinsic property of the cells. RNase H1 is not likely to be a major player in the antisense ODN-mediated degradation of target mRNAs. RNase H2 is involved in the activity assayed in vitro. The presence of cell-type specific factors affecting the activity and localization of RNase H2 is strongly suggested.

To estimate the proportion of patients with familial hypercholesterolaemia (FH) who were identified with hypercholesterolaemia in general practice prior to screening by means of pedigree research and DNA analysis by the National Foundation for the Identification of Familial Hypercholesterolemia (StOEH).Retrospective.General practice files of FH patients, diagnosed through genetic screening by the StOEH in 1992-1997 whose general practitioner's (GP's) practice in Amsterdam, Haarlem or Alkmaar, were studied for cholesterol and FH related information documented in the period prior to the screening.Out of the 121 persons selected 80 agreed to the study; one GP refused to co-operate. There was no difference between respondents and non respondents with regard to age, sex or domicile of the GP. In 48 of 79 (61%) general practice files studied, cholesterol measurements were reported prior to screening; 39 patients (49%) had hypercholesterolaemia and 29 (37%) were being treated with cholesterol lowering drugs. Mean age of the FH patients who had no record of their cholesterol levels was 25.1 years (SD: 17.0) at the time of screening, 22 years younger than the mean age of FH patients who did have cholesterol levels on record prior to screening (47.1 (SD: 18.4); p0.0001).Of the FH patients identified through family based genetic screening especially the younger FH patients are newly brought to the attention of their GP.

The lack of specificity of cancer treatment causes damage to normal cells as well, which limits the therapeutic range. To circumvent this problem one would need to use an absolute difference between normal cells and cancer cells as therapeutic target. Such a difference exists in the genome of all individuals suffering from a tumor that is characterized by loss of genetic material [loss of heterozygosity (LOH)]. Due to LOH, the tumor is hemizygous for a number of genes, whereas the normal cells of the individual are heterozygous for these genes. Theoretically, polymorphic sites in these genes can be utilized to selectively target the cancer cells with an antisense oligonucleotide, provided that it can discriminate the alleles and inhibit gene expression. Furthermore, the targeted gene should be essential for cell survival, and 50% gene expression sufficient for the cell to survive. This will allow selective killing of cancer cells without concomitant toxicity to normal cells. As an initial step in the experimental test of this putative selective cancer cell therapy, we have developed a set of antisense phosphorothioate oligonucleotides which can discriminate the two alleles of a polymorphic site in the gene encoding the large subunit of RNA polymerase II. Our data show that the exact position of the antisense oligonucleotide on the mRNA is of essential importance for the oligo-nucleotide to be an effective inhibitor of gene expression. Shifting the oligonucleotide position only a few bases along the mRNA sequence will completely abolish the inhibitory activity of the antisense oligonucleotide. Reducing the length of the oligonucleotides to 16 bases increases the allele specificity. This study shows that it is possible to design oligonucleotides that selectively target the matched allele, whereas the expression level of the mismatched allele, that differs by one nucleotide, is only slightly affected.

To determine the frequency distributions of serial interval and incubation period of tuberculosis within 4 years of transmission, and to identify correlates of serial intervals and incubation periods.DNA fingerprints were obtained for all isolates from all culture-positive patients notified in The Netherlands from 1993 to 1996. Patient information was obtained from the National Tuberculosis Register. Results from contact investigations were provided by public health services. Source cases and secondary cases of tuberculosis were identified, based on 1) identical DNA fingerprints, and 2) epidemiological confirmation of contact. Under-representation of long intervals were corrected for by weighting cases.A total of 69 source-secondary case couples were identified. The geometric mean serial interval was 29.5 weeks (95% confidence interval [CI] 22.8-38.2 weeks) and the geometric mean incubation period 20.8 weeks (95% CI 15.5-27.8 weeks). Serial intervals and incubation periods tended to increase with age (P0.05). Three secondary cases with human immunodeficiency virus infection showed very short incubation periods (P0.05).Using a new methodology, the distribution of incubation periods of tuberculosis gave results consistent with earlier studies.