The effects and costs of breast cancer screening

In 1986, the Dutch Ministry of Welfare, Health and Cultural Affairs asked a research group to investigate the expected effect of breast cancer screening on mortality and possibly morbidity, if implemented in the Netherlands. The research group consisted of members from 3 centres, the Dept. of Public Health (Erasmus Universiteit Rotterdam), the Dept. of Public Health and Epidemiology/ Preventicon (Rijksuniversiteit Utrecht) and the Dept. of Epidemiology/ Radiology (Katholieke Universiteit Nijmegen). Data from the two Dutch breast cancer screening projects, the DOM-projects in Utrecht (Rombach, 1980; Collette et a!., 1984; de Waard et a!., 1984) and the Nijmegen project (Hendriks, 1982; Verbeek et a!., 1984; Peeters, 1989) which started in 1974/1975, was made available in order to first establish more precise estimates for the parameters in the above mentioned model for the disease process of breast cancer and screening in the Netherlands. Together with research on the cost, one of the first Dutch cost-effectiveness analyses in health care was started.With the research described in this thesis, both the concept of screening and the underlying model earlier described have been extended to include the impact on almost all aspects after or beyond the screening examination itself: impact on advanced disease late in life, on assessment and primary treatment for women and for health care, on quality of life, impact on financial cost and impact on the situation of the disease in a population outside the invited or screened grou

Mammographic screening: evidence from randomised controlled trials

BACKGROUND: All randomised breast cancer screening trials have shown a reduction in breast cancer mortality in the 'invited for mammography' screening arm compared with the 'control arm' for women aged 50 years and older at randomisation (overall 25%). However, individually published point estimates differ and concern has been raised about methodological quality and outcome measures. Materials and Methods Review of the evidence on breast cancer mortality reduction and discussion of the causes of difference in point estimates in the five Swedish and Canadian trials. A summary of the prerequisites for methodological quality and its available evidence from the trials is given. Data to support breast cancer mortality as a correct outcome measure are presented. RESULTS: There is no reason not to use breast cancer mortality as an outcome measure for trials intended to reduce breast cancer mortality, both from a clinical and a methodological point of view. Everything possible was performed in these trials in order to determine this outcome measure as accurately as possible. The fact that a few of the trials showed a relatively large breast cancer mortality reduction and others far lower reduction rates is irrelevant, if one does not consider the background situation in the region before the trial started, the design of the trial or quality of screening. CONCLUSIONS: There seems no reason to change or halt the current nation-wide population-based screening programmes. Nor is there any justifiable reason for negative reports towards women or professionals

The drugs of sleeping sickness: their mechanisms of action and resistance, and a brief history

With the incidence of sleeping sickness in decline and genuine progress being made towards the WHO goal of eliminating sleeping sickness as a major public health concern, this is a good moment to evaluate the drugs that ‘got the job done’: their development, their limitations and the resistance that the parasites developed against them. This retrospective looks back on the remarkable story of chemotherapy against trypanosomiasis, a story that goes back to the very origins and conception of chemotherapy in the first years of the 20 century and is still not finished today

Drug resistance in protozoan parasites

As with all other anti-infectives (antibiotics, anti-viral drugs, and anthelminthics), the limited arsenal of anti-protozoal drugs is being depleted by a combination of two factors: increasing drug resistance and the failure to replace old and often shamefully inadequate drugs, including those compromised by (cross)-resistance, through the development of new anti-parasitics. Both factors are equally to blame: a leaking bathtub may have plenty of water if the tap is left open; if not, it will soon be empty. Here, I will reflect on the factors that contribute to the drug resistance emergency that is unfolding around us, specifically resistance in protozoan parasites

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (Berenil®), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (MPXR) is the result of loss of a separate High Affinity Pentamidine Transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the “selectivity region” of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this remarkable ability

Bracing patients with idiopathic scoliosis: Design of the Dutch randomized controlled treatment trial

BACKGROUND: The effectiveness of bracing patients with IS has not yet been convincingly established due to a lack of RCTs. Some authors suggest that their results confirm that bracing is effective; others conclude that the effectiveness of bracing is doubtful or recommend a RCT. The aim of this study was to establish whether bracing patients with idiopathic scoliosis (IS) in an early stage will result in at least 5 degrees less mean progression of the curvature compared to the control group after two years of follow-up. METHODS: A randomized controlled trial was designed. Eligible patients are girls and boys in the age group 8–15 years whose diagnosis of IS has been established by an orthopedic surgeon, who have not yet been treated by bracing or surgery, and for whom further growth of physical height is still expected based on medical examination and maturation characteristics (Risser ≤ 2). The Cobb angle of the eligible patient should either be minimally 22 and maximally 29 degrees with established progression of more than 5 degrees, or should be minimally 30 and maximally 35 degrees; established progression for the latter is not necessary. A total of 100 patients will be included in this trial. The intervention group will be treated with full-time Boston brace wear; the control group will not be braced. Every four months, each patient will have a physical and an X-ray examination. The main outcomes will be the Cobb angle two years after inclusion and health-related quality of life. DISCUSSION: The results of this trial will be of great importance for the discussion on early treatment for scoliosis. Furthermore, the result will also be important for screening for scoliosis policies. TRIAL REGISTRATION: Nederlands Trialregister ISRCTN3696473

The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

Kinetoplastids are unicellular, eukaryotic, flagellated protozoans containing the eponymous kinetoplast. Within this order, the family of trypanosomatids are responsible for some of the most serious human diseases, including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.), and leishmaniasis (Leishmania spp). Although cAMP is produced during the life cycle stages of these parasites, its signaling pathways are very different from those of mammals. The absence of G-protein-coupled receptors, the presence of structurally different adenylyl cyclases, the paucity of known cAMP effector proteins and the stringent need for regulation of cAMP in the small kinetoplastid cells all suggest a significantly different biochemical pathway and likely cell biology. However, each of the main kinetoplastid parasites express four class 1-type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. To date, only TbrPDEB, expressed as two slightly different isoforms TbrPDEB1 and B2, has been found to be essential when ablated. Although the genomes contain reasonably well conserved genes for catalytic and regulatory domains of protein kinase A, these have been shown to have varied structural and functional roles in the different species. Recent discovery of a role of cAMP/AMP metabolism in a quorum-sensing signaling pathway in T. brucei, and the identification of downstream cAMP Response Proteins (CARPs) whose expression levels correlate with sensitivity to PDE inhibitors, suggests a complex signaling cascade. The interplay between the roles of these novel CARPs and the quorum-sensing signaling pathway on cell division and differentiation makes for intriguing cell biology and a new paradigm in cAMP signal transduction, as well as potential targets for trypanosomatid-specific cAMP pathway-based therapeutics

Trypanosoma brucei methylthioadenosine phosphorylase protects the parasite from the antitrypanosomal effect of deoxyadenosine

Trypanosoma brucei causes African sleeping sickness for which no vaccine exists and available treatments are of limited use due to their high toxicity or lack of efficacy. T. brucei cultivated in the presence of deoxyadenosine accumulates high levels of dATP in an adenosine kinase-dependent process and dies within a few hours. Here we show that T. brucei treated with 1 mM deoxyadenosine accumulates higher dATP levels than mammalian cells but that this effect diminishes quickly as the concentration of the deoxynucleoside decreases. Radioactive tracer studies showed that the parasites are partially protected against lower concentrations of deoxyadenosine by the ability to cleave it and use the adenine for ATP synthesis. T. brucei methylthioadenosine phosphorylase (TbMTAP) was found to be responsible for the cleavage as indicated by the phosphate dependence of deoxyadenosine cleavage in T. brucei cell extracts and increased deoxyadenosine sensitivity in TbMTAP knockdown cells. Recombinant TbMTAP exhibited higher turnover number (kcat) and Km values for deoxyadenosine than for the regular substrate, methylthioadenosine. One of the reaction products, adenine, inhibited the enzyme, which might explain why TbMTAP-mediated protection is less efficient at higher deoxyadenosine concentrations. Consequently, T. brucei grown in the presence of adenine demonstrated increased sensitivity to deoxyadenosine. For deoxyadenosine/adenosine analogues to remain intact and be active against the parasite, they need to either be resistant to TbMTAP-mediated cleavage, which is the case with the three known antitrypanosomal agents adenine arabinoside, tubercidin, and cordycepin, or they need to be combined with TbMTAP inhibitors