Schistosomiasis epidemiology and control: how did we get here and where should we go?

Although a disease of great antiquity, scientific studies of schistosomiasis began only 150 years ago. The complete life-cycle was not described until just before the First World War, making it possible at last to plan proper community control programmes. Inadequate tools prevented their effective implementation until well after the Second World War when new tools became available, thanks to the newly formed World Health Organization. Molluscicides spearheaded control programmes until the late 1970s but were then replaced by the newly developed, safe drugs still used today. Whatever the method used, the initial goal of eradication was, in the light of experience and cost, gradually replaced by less ambitious targets; first to stop transmission and then to reduce morbidity. The most successful programmes combined several methods to minimise reinfection after chemotherapy. Comparisons between different programmes are difficult without using appropriate, standardised diagnostic techniques and the correct epidemiological measurements. Some examples will be presented, mainly from our studies on Schistosoma mansoni in Kenya. Drug resistance on a scale comparable with malaria has not occurred in schistosomiasis but the likely withdrawal of all drugs except praziquantel leaves its control extremely vulnerable to this potential problem. An effective, affordable vaccine for use in endemic countries is unlikely to be ready for at least 5 years, and developing strategies for its use could take a further decade or more, judging from experience with drugs and molluscicides. In the interim, by analogy with malaria, the most cost-effective approach would the use of drugs combined with other methods to stop transmission, including molluscicides. The cost of molluscicides needs to be reduced and fears allayed about their supposedly adverse ecological effects.

Progresión tumoral y búsqueda de nuevas dianas terapéuticas en la familia de tumores del sarcoma de Ewing: función biológica de la caveolina-1

El sarcoma de Ewing es el segundo tumor óseo infantil más frecuente y presenta una alta incidencia de enfermedad metastática. Este tipo de tumores presentan una traslocación génica característica que da origen a una proteína de fusión, normalmente EWS/FLI1. Esta proteína de fusión actúa como factor de transcripción aberrante regulando la expresión de diferentes genes implicados en la iniciación, mantenimiento y progresión del tumor. Nuestro grupo describió como uno de estos genes diana a la caveolina 1 (CAV1) describiendo además su papel determinante en el fenotipo maligno del sarcoma de Ewing, en la tumorigénesis y en la resistencia a apoptosis inducida por quimioterapia. Para investigar el papel concreto de CAV1 en el proceso metastático de este sarcoma, creamos un modelo de baja expresión de CAV1 en líneas celulares de sarcoma de Ewing y determinamos cambios en su capacidad migratoria, invasiva y metastática. En los ensayos in vitro hallamos una menor capacidad migratoria de las células knockdown de CAV1 y una reducción en la expresión de MMP9 y en la actividad de MMP2. La regulación de la actividad de MMP2 parece estar relacionada con la posible regulación que ejerce CAV1 en la función de MT1-MMP, proteína fundamental para la activación de MMP2. Por otro lado, en este estudio proponemos que CAV1 promueve la expresión de MMP9 tanto transcripcionalmente, regulando la vía de señalización ERK1/2, como a nivel post-transcripcional regulando la vía RSK1/rpS6. Además, en los ensayos de metástasis experimental in vivo las células knockdown de CAV1 presentaron una menor incidencia de metástasis pulmonar, hecho que correlacionó con una disminución en la expresión de SPARC, una proteína de adhesión importante en procesos metastáticos. En resumen, nuestros resultados evidencian la importancia de CAV1 en el proceso metastático del sarcoma de Ewing.

The impact of repeated treatment with praziquantel of schistosomiasis in children under six years of age living in an endemic area for Schistosoma haematobium infection

Praziquantel was given every eight weeks for two years to children aged under six years of age, living in a Schistosoma haematobium endemic area. Infection with S. haematobium and haematuria were examined in urine and antibody profiles (IgA, IgE, IgM, IgG1, IgG2, IgG3, and IgG4) against S. haematobium adult worm and egg antigens were determined from sera collected before each treatment. Chemotherapy reduced infection prevalence and mean intensity from 51.8% and 110 eggs per 10 ml urine, respectively, before starting re-treatment programme to very low levels thereafter. Praziquantel is not accumulated after periodic administration in children. Immunoglobulin levels change during the course of treatment with a shift towards 'protective' mechanisms. The significant changes noted in some individuals were the drop in 'blocking' IgG2 and IgG4 whereas the 'protecting' IgA and IgG1 levels increased. The antibody profiles in the rest of the children remained generally unchanged throughout the study and no haematuria was observed after the second treatment. The removal of worms before production of large number of eggs, prevented the children from developing morbidity.

Replacing oxamniquine by praziquantel against Schistosoma mansoni infection in a rural community from the sugar-cane zone of Northeast Brazil: an epidemiological follow-up

A group of 52 villagers was followed-up for three years regarding Schistosoma mansoni infection. All villagers were periodically surveyed by the Kato-Katz method. In March 1997 and March 1998 the positives were treated with oxamniquine (15-20 mg/kg), and in March 1999, with praziquantel (60 mg/kg). All infection indices decreased substantially between March 1999 and March 2000: prevalence of infection (from 32.7% to 21.2%), prevalence of moderate/heavy infection (from 7.7% to 1.9%), intensity of infection (from 23.1 epg to 7.4 epg) and reinfection (from 35.7% to 14.3%). Negativation increased from 53.8 to 82.4. An optimistic prognostic is assumed in the short term for the introduction of praziquantel in the study area.

Regional Advisory Committee on Cancer - Second Report 2002 (PDF 132 KB)

Regional Advisory Committee on Cancer (RACC) was established in 1997 to carry forward the recommendations of the Campbell Report of 1996 and to provide advice to the Department of Health and Social Services on the future development of cancer services. The Committee meets twice a year and its membership (Appendix I) is an indication of the wide range of interests involved in Cancer Care across the community. This report records some of the key developments in cancer services over the last 3 years. åÊ Significant progress has been made toward developing a high quality and integrated cancer care network. All five Cancer Units are now operational with chemotherapy and outpatient services for the most common forms of cancer are delivered from these locations. Agreement to the start of the new Cancer Centre, at the Belfast City Hospital, currently estimated to cost å£58m, is expected shortly. As a temporary expedient two additional therapy machines will be installed in Belvoir Park Hospital to increase capacity while the building of the new Cancer Centre proceeds. åÊ To deliver high quality cancer care the workforce needs to continue to expand. This requires increasing investment in the training of professional staff in the context of an already difficult HPSS labour market. The development of the five Cancer Units has increased staff mobility in the short-term, drawing skilled staff away from the centre who have been difficult to replace. At the same time increasing numbers of patients are being offered effective therapies at both the Cancer Units and the Centre. åÊ This report contains a review of selected developments in cancer care. The first section introduces the Memorandum of Understanding and the Tripartite Agreement between the National Cancer Institute of the USA and the Health Departments both North and South. This is a unique international partnership, which promises to bring very significant advantages to both the service and research communities across the Island. åÊ åÊ åÊ

Y-688, a new quinolone active against quinolone-resistant Staphylococcus aureus: lack of in vivo efficacy in experimental endocarditis.

Y-688 is a new fluoroquinolone with increased activity against ciprofloxacin-resistant staphylococci. The MICs of Y-688 and other quinolones were determined for 58 isolates of ciprofloxacin-resistant and methicillin-resistant Staphylococcus aureus (MRSA). The MICs at which 50% and 90% of bacteria were inhibited were >/=128 and >/=128 mg/liter, respectively, for ciprofloxacin, 16 and 32 mg/liter, respectively, for sparfloxacin, and 0.25 and 1 mg/liter, respectively, for Y-688. This new quinolone was further tested in rats with experimental endocarditis due to either of two isolates of ciprofloxacin-resistant MRSA (namely, P8/128 and CR1). Infected animals were treated for 3 days with ciprofloxacin, vancomycin, or Y-688. Antibiotics were administered through a computerized pump to simulate human-like pharmacokinetics in the serum of rats. The anticipated peak and trough levels of Y-688 were 4 and 1 mg/liter at 0.5 and 12 h, respectively. Treatment with ciprofloxacin was ineffective. Vancomycin significantly decreased vegetation bacterial counts for both organisms (P less, similar 0.05). In contrast, Y-688 only marginally decreased vegetation bacterial counts (P greater, similar 0.05). Moreover, several vegetation that failed Y-688 treatment grew staphylococci for which the MICs of the test antibiotic were increased two to eight times. Y-688 also selected for resistance in vitro, and isolates for which the MICs were increased eight times emerged at a frequency of ca. 10(-8). Thus, in spite of its low MIC for ciprofloxacin-resistant MRSA, Y-688 failed in vivo and its use carried the risk of resistance selection. The fact that ciprofloxacin-resistant staphylococci became rapidly resistant to this potent new drug suggests that the treatment of ciprofloxacin-resistant MRSA with new quinolones might be more problematic than expected.

Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma?

PURPOSE: Patients with hereditary retinoblastoma (Rb) develop in 4%-8% a malignant midline tumor called trilateral Rb (TRb). We report in this study on benign pineal cysts observed in patients investigated for TRb. PATIENTS AND METHODS: Between September 1990 and December 2001, 172 patients were screened for TRb. Ninty-five had bilateral, 77 unilateral disease. The median age at diagnosis of Rb was 7 months (range 1-26). Treatment included enucleation, local treatment with cryotherapy or photocoagulation, first-line chemotherapy (CT), thermo-chemotherapy (TCT), Ruthenium plaque, and, rarely, external beam radiation (EBR). RESULTS: TRb was found in 5/95 patients (5.3%) with bilateral disease. Interestingly, five other patients (5.3%) presented a pineal cyst on magnetic resonance imaging (MRI). No cysts were recorded in the 77 patients with unilateral disease. This difference was statistically significant (P < 0.05). The median age at diagnosis of the pineal cyst was 26 months (range 16-80), much younger than reported in literature for healthy children. Four of five patients with TRb died of the disease, while all the patients with pineal cysts remained stable and asymptomatic during a median follow-up of 41 months (range 37-54). CONCLUSIONS: This report describes benign cystic lesions of the pineal gland in patients with hereditary Rb, suggesting a benign variant of TRb. Underlying possible pathogenetic mechanisms are discussed.

Molecular Modeling Approaches for Determining Gene Function: application to a Putative Poly-A Binding Protein from Leishmania amazonensis (LaPABP)

The great expansion in the number of genome sequencing projects has revealed the importance of computational methods to speed up the characterization of unknown genes. These studies have been improved by the use of three dimensional information from the predicted proteins generated by molecular modeling techniques. In this work, we disclose the structure-function relationship of a gene product from Leishmania amazonensis by applying molecular modeling and bioinformatics techniques. The analyzed sequence encodes a 159 aminoacids polypeptide (estimated 18 kDa) and was denoted LaPABP for its high homology with poly-A binding proteins from trypanosomatids. The domain structure, clustering analysis and a three dimensional model of LaPABP, basically obtained by homology modeling on the structure of the human poly-A binding protein, are described. Based on the analysis of the electrostatic potential mapped on the model's surface and conservation of intramolecular contacts responsible for folding stabilization we hypothesize that this protein may have less avidity to RNA than it's L. major counterpart but still account for a significant functional activity in the parasite. The model obtained will help in the design of mutagenesis experiments aimed to elucidate the mechanism of gene expression in trypanosomatids and serve as a starting point for its exploration as a potential source of targets for a rational chemotherapy.

Altered Response of Strain of Schistosoma mansoni to Oxamniquine and Praziquantel

The susceptibility of a fourth generation Ouh strain (Paranapanema Valley, São Paulo, Brazil) of Schistosoma mansoni to oxamniquine (OXA) and praziquantel (PZQ) was studied. Ten groups of 13 female albino mice each were infected with 70 cercariae per animal. These mice were medicated orally on the 50th day after infection. Five groups were given OXA doses of 0, 100, 200, 300 and 400 mg/kg (single doses) and the rest were treated with PZQ doses of 0, 100, 200, and 250 mg/kg/5 days. Each group was sub-divided: 8 animals underwent perfusion after 15 days treatment, 5 mice followed up for oviposition and their feces were tested every 15 days for miracidia hatching. The efficacy of the OXA doses of 100 and 200 mg/kg was 66% and 91.4%, respectively and for the 100 mg/kg PZQ dose it was 90.1%. The follow-up groups with 100 and 200 mg/kg of OXA and PZQ, 100 and 150 mg/kg, showed that they re-established the oviposition after a period of 60 to 75 days of treatment. The ED50 was 69.6mg/kg OXA and 39.4 mg/kg PZQ. The results show the tolerance of the Ouh strain to a dose of 100 mg with both drugs and they appoint the need for a dose review during the follow up of the oviposition and in monitoring phenomena in the field.

Longitudinal Study on the Natural Infection of Biomphalaria straminea and B. glabrata by Schistosoma mansoni in an Endemic Area of Schistosomiasis in Pernambuco, Brazil

The abundance of snail hosts and the rates of infection with Schistosoma mansoni were monitored monthly for four years in two representative localities subjected to repeated chemotherapy of infected persons. Snail abundance varied from 1.0 to 4.4 collected per person/minute/station for Biomphalaria straminea and from 0.1 to 7.0 for B. glabrata. Infection rates of snails in nature varied from 0% to 15% for the former and from 0% to 70% for the latter species. Human infection increased from 35.5% to 61.9% in the locality occupied by B. straminea, and decreased from 40.3% to 20.8% in that occupied by B. glabrata. No relationship could be detected between human infection and the snail variables. Despite seasonal variations, natural infection persisted throughout the monitoring period in both snail species. It reached remarkably high levels in B. straminea when compared to those obtained by other authors probably because of differences in methodology. It is recommended that longitudinal studies should be carried out focally and periodically to avoid underestimating the prevalence of schistosome infection in snails.

Anti-angiogenic therapies for metastatic colorectal cancer.

BACKGROUND: Angiogenesis inhibitors have been developed to block tumour angiogenesis and target vascular endothelial cells. While some of them have already been approved by the health authorities and are successfully integrated into patient care, many others are still under development, and the clinical value of this approach has to be established. OBJECTIVES: To assess the efficacy and toxicity of targeted anti-angiogenic therapies, in addition to chemotherapy, in patients with metastatic colorectal cancer. Primary endpoints are both progression-free and overall survival. Response rates, toxicity and secondary resectability were secondary endpoints. Comparisons were first-line chemotherapy in combination with angiogenesis inhibitor, to the same chemotherapy without angiogenesis inhibitor; and second-line chemotherapy, to the same chemotherapy without angiogenesis inhibitor. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, as well as proceedings from ECCO, ESMO and ASCO until November 2008. In addition, reference lists from trials were scanned, experts in the field and drug manufacturers were contacted to obtain further information. SELECTION CRITERIA: Randomized controlled trials on targeted anti-angiogenic drugs in metastatic colorectal cancer (MCRC). DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed, according to a previously published protocol. Because individual patient data was not provided, aggregate data had to be used for the analysis. Summary statistics for the primary endpoints were hazard ratios (HR's) and their 95% confidence intervals. MAIN RESULTS: At present, eligible first line trials for this meta-analysis were available for bevacizumab (5 trials including 3101 patients) and vatalanib (1 trial which included 1168 patients). The overall HR s for PFS (0.61, 95% CI 0.45 - 0.83) and OS (0.81, 95% 0.73 - 0.90) for the comparison of first-line chemotherapy, with or without bevacizumab, confirms significant benefits in favour of the patients treated with bevacizumab. However, the effect on PFS shows significant heterogeneity. For second-line chemotherapy, with or without bevacizumab, a benefit in both PFS (HR 0.61, 95% CI 0.51 - 0.73) and OS (HR 0.75, 95% CI 0.63-0.89) was demonstrated in a single, randomized trial. While differences in treatment-related deaths and 60-day mortality were not significant, higher incidences in grade III/IV hypertension, arterial thrombembolic events and gastrointestinal perforations were observed in the patients treated with bevacizumab. For valatanib, currently available data showed a non-significant benefit in PFS and OS. AUTHORS' CONCLUSIONS: The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first-and second-line therapy.

Promoter and transcription analysis of penicillin-binding protein genes in Streptococcus gordonii.

An optimally cross-linked peptidoglycan requires both transglycosylation and transpeptidation, provided by class A and class B penicillin-binding proteins (PBPs). Streptococcus gordonii possesses three class A PBPs (PBPs 1A, 1B, and 2A) and two class B PBPs (PBPs 2B and 2X) that are important for penicillin resistance. High-level resistance (MIC, > or =2 microg/ml) requires mutations in class B PBPs. However, although unmutated, class A PBPs are critical to facilitate resistance development (M. Haenni and P. Moreillon, Antimicrob. Agents Chemother. 50:4053-4061, 2006). Thus, their overexpression might be important to sustain the drug. Here, we determined the promoter regions of the S. gordonii PBPs and compared them to those of other streptococci. The extended -10 box was highly conserved and complied with a sigma(A)-type promoter consensus sequence. In contrast, the -35 box was poorly conserved, leaving the possibility of differential PBP regulation. Gene expression in a penicillin-susceptible parent (MIC, 0.008 microg/ml) and a high-level-resistant mutant (MIC, 2 microg/ml) was monitored using luciferase fusions. In the absence of penicillin, all PBPs were constitutively expressed, but their expression was globally increased (1.5 to 2 times) in the resistant mutant. In the presence of penicillin, class A PBPs were specifically overexpressed both in the parent (PBP 2A) and in the resistant mutant (PBPs 1A and 2A). By increasing transglycosylation, class A PBPs could promote peptidoglycan stability when transpeptidase is inhibited by penicillin. Since penicillin-related induction of class A PBPs occurred in both susceptible and resistant cells, such a mutation-independent facilitating mechanism could be operative at each step of resistance development.

Toxic and drug-induced peripheral neuropathies: updates on causes, mechanisms and management.

PURPOSE OF REVIEW: This review discusses publications highlighting current research on toxic, chemotherapy-induced peripheral neuropathies (CIPNs), and drug-induced peripheral neuropathies (DIPNs). RECENT FINDINGS: The emphasis in clinical studies is on the early detection and grading of peripheral neuropathies, whereas recent studies in animal models have given insights into molecular mechanisms, with the discovery of novel neuronal, axonal, and Schwann cell targets. Some substances trigger inflammatory changes in the peripheral nerves. Pharmacogenetic techniques are underway to identify genes that may help to predict individuals at higher risk of developing DIPNs. Several papers have been published on chemoprotectants; however, to date, this approach has not been shown effective in clinical trials. SUMMARY: Both length and nonlength-dependent neuropathies are encountered, including small-fiber involvement. The introduction of new diagnostic techniques, such as excitability studies, skin laser Doppler flowmetry, and pharmacogenetics, holds promise for early detection and to elucidate underlying mechanisms. New approaches to improve functions and quality of life in CIPN patients are discussed. Apart from developing less neurotoxic anticancer therapies, there is still hope to identify chemoprotective agents (erythropoietin and substances involved in the endocannabinoid system are promising) able to prevent or correct painful CIPNs.

Avancées recentes dans le traitement des carcinomes corticosurrénaliens [Recent advances in the treatment of adrenocortical carcinomas].

Adrenocortical carcinomas are rare and aggressive malignant tumors, with an incidence of 1 to 2 cases per million inhabitants. Their diagnosis is made in three clinical situations: during the work up of a syndrome of hormonal hypersecretion, during the work up of locoregional symptoms, or incidentally during an unrelated radiological procedure. Surgery is usually indicated except in situations of advanced metastatic disease. Adjuvant chemotherapy with mitotane is associated with a significant increase in disease-free survival when the drug is administered at adequate therapeutic dosage. Novel anti-mitotic therapies have recently been described for treating recurrent adrenocortical carcinoma under mitotane treatment, but their overall efficacy remains unsatisfactory.