41 results on '"Terlouw D"'
Search Results
2. Complex interactions between malaria and malnutrition: a systematic literature review
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Das, D, Grais, R F, Okiro, E A, Stepniewska, K, Mansoor, R, van der Kam, S, Terlouw, D J, Tarning, J, Barnes, K I, and Guerin, P J
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- 2018
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3. Mismatch repair deficiency and MUTYH variants in small intestine-neuroendocrine tumors
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Helderman, N.C., Elsayed, F.A., Wezel, T. van, Terlouw, D., Langers, A.M.J., Egmond, D. van, Kilinc, G., Hristova, H., Sarasqueta, A.F., Morreau, H., Nielsen, M., Suerink, M., and Pathology
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congenital, hereditary, and neonatal diseases and abnormalities ,MUTYH ,Brain Neoplasms ,Colorectal Neoplasms, Hereditary Nonpolyposis ,DNA Mismatch Repair ,Pathology and Forensic Medicine ,DNA Glycosylases ,Neuroendocrine Tumors ,Lynch syndrome ,Neoplastic Syndromes, Hereditary ,Intestine, Small ,Humans ,Small intestine-neuroendocrine tumors ,Colorectal Neoplasms ,MutL Protein Homolog 1 ,Cancer genetics ,Mismatch repair deficiency ,Germ-Line Mutation ,Mismatch Repair Endonuclease PMS2 - Abstract
& nbsp;Small intestine-neuroendocrine tumors (SI-NETs) are one of the most common tumors of the small bowel. Despite an increasing incidence, the exact mechanisms driving underlying pathology remain to be determined. Interestingly, recent studies linked the development of (SI-)NETs to both Lynch syndrome (LS) and MUTYH variants. If confirmed, these associations would have important consequences for treatment. In this study we therefore investigated the prevalence of mismatch repair (MMR) deficiency and MUTYH variants in 64 primary resected SI-NETs. Immunohistochemistry was used to assess the expression of the MMR genes, and competitive allele-specific PCR (KASPar) targeting two hotspot MUTYH variants [p.(Tyr179Cys), p.(Gly396Asp)] was performed to determine their prevalence in SI-NETs. Strikingly, all 64 SI-NETs stained positive for MSH6 and PMS2, indicating & nbsp;MMR proficiency. In addition, no MUTYH hotspot variant was found in any of the 64 SI-NETs. As such, these results do not support an association between SI-NET development and LS or MUTYH variants. In order to gain insight into SI-NET pathogenesis and optimally manage patients, future research should therefore focus on other candidate genes. (C) 2022 Published by Elsevier Inc
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- 2022
4. APCmosaicism, not always isolated: two first-degree relatives with apparently distinctAPCmosaicism
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Terlouw, D., Hes, F.J., Suerink, M., Boot, A., Langers, A.M.J., Tops, C.M., Leerdam, M.E. van, Asperen, C.J. van, Rozen, S.G., Bijlsma, E.K., Wezel, T. van, Morreau, H., and Nielsen, M.
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Gastroenterology - Published
- 2022
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5. Efficacy and safety of artemether–lumefantrine as treatment for Plasmodium falciparum uncomplicated malaria in adult patients on efavirenz-based antiretroviral therapy in Zambia: an open label non-randomized interventional trial
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Banda, C, Chaponda, M, Mukaka, M, Mulenga, M, Hachizovu, S, Kabuya, J, Mulenga, J, Sikalima, J, Kalilani-Phiri, L, Terlouw, D, Khoo, S, Lalloo, D, and Mwapasa, V
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Adult ,Cyclopropanes ,Male ,Drug–drug interactions ,lcsh:Arctic medicine. Tropical medicine ,Adolescent ,lcsh:RC955-962 ,Plasmodium falciparum ,Zambia ,HIV Infections ,Polymerase Chain Reaction ,lcsh:Infectious and parasitic diseases ,Antimalarials ,Young Adult ,parasitic diseases ,Humans ,lcsh:RC109-216 ,Prospective Studies ,Malaria, Falciparum ,Aged ,Human immunodeficiency virus ,Research ,Artemether, Lumefantrine Drug Combination ,Middle Aged ,Benzoxazines ,Malaria ,Alkynes ,Reverse Transcriptase Inhibitors ,Anti-retroviral drugs ,Female ,Artemether–lumefantrine - Abstract
Background HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Artemether–lumefantrine (AL) is the most commonly used ACT for treatment of falciparum malaria in Africa but there is limited evidence on the safety and efficacy of AL in HIV-infected individuals on ART, among whom drug–drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events was assessed in HIV-infected individuals on efavirenz-based ART with uncomplicated falciparum malaria treated with AL. Methods A prospective, open label, non-randomized, interventional clinical trial was conducted at St Paul’s Hospital in northern Zambia, involving 152 patients aged 15–65 years with uncomplicated falciparum malaria, who were on efavirenz-based ART. They received a 3-day directly observed standard treatment of AL and were followed up until day 63. Day-42 polymerase chain reaction (PCR)-corrected ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat population. Results Enrolled patients had a baseline geometric mean (95% CI) parasite density of 1108 (841–1463) parasites/µL; 16.4% (25/152) of the participants had a recurrent malaria episode by day 42. However, PCR data was available for 17 out of the 25 patients who had malaria recurrence. Among all the 17 patients, PCR findings demonstrated malaria re-infection, making the PCR-adjusted day-42 ACPR 100% in the 144 patients who could be evaluated. Even when eight patients with missing PCR data were considered very conservatively as failures, the day-42 ACPR was over 94%. None of the participants, disease or treatment characteristics, including day-7 lumefantrine concentrations, predicted the risk of malaria recurrence by day 42. AL was well tolerated following administration. There were only two cases of grade 3 neutropaenia and one serious adverse event of lobar pneumonia, none of which was judged as probably related to intake of AL. Conclusions AL was well tolerated and efficacious in treating uncomplicated falciparum malaria in HIV co-infected adults on efavirenz-based ART. However, a higher than anticipated proportion of participants experienced malaria re-infection, which highlights the need for additional malaria prevention measures in this sub-population after treatment with AL. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013. https://pactr.samrc.ac.za/Search.aspx Electronic supplementary material The online version of this article (10.1186/s12936-019-2818-7) contains supplementary material, which is available to authorized users.
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- 2019
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6. Progression of stunting and its predictors among school-aged children in western Kenya
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Friedman, J F, Phillips-Howard, P A, Mirel, L B, Terlouw, D J, Okello, N, Vulule, J M, Hawley, W A, Nahlen, B L, and ter Kuile, F
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- 2005
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7. Mosaic APC mutations in patients with mild polyposis phenotypes
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Terlouw, D., Suerink, M., Tops, C., Alexandra Langers, Hes, F. J., Ten Broeke, S., Dams, L., Wezel, T., Morreau, H., Nielsen, M., Clinical sciences, Medical Genetics, and Faculty of Law and Criminology
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- 2019
8. Recognition of pallor associated with severe anaemia by primary caregivers in western Kenya
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Desai, M. R., Phillips-Howard, P. A., Terlouw, D. J., Wannemuehler, K. A., Odhacha, A., Kariuki, S. K., Nahlen, B. L., and ter Kuile, F. O.
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- 2002
9. Pharmacokinetics of Piperaquine and Safety Profile of Dihydroartemisinin-Piperaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults
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Banda, C, Dzinjalamala, F, Mukaka, M, Mallewa, J, Maiden, V, Terlouw, D, Lalloo, D, Khoo, S, and Mwapasa, V
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Adult ,Cyclopropanes ,Male ,antiretroviral therapy ,malaria ,virus diseases ,HIV Infections ,Clinical Therapeutics ,Middle Aged ,antiretroviral agents ,Artemisinins ,Benzoxazines ,piperaquine ,Antimalarials ,Anti-Retroviral Agents ,Alkynes ,Quinolines ,Humans ,Female ,Nevirapine - Abstract
There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus-infected (HIV-positive [HIV+]) individuals taking antiretroviral therapy (ART). In a two-step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared the area under the concentration-time curve from days 0 to 28 (AUC0–28 days) and the safety outcomes of piperaquine among malaria-uninfected HIV+ adults., There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus-infected (HIV-positive [HIV+]) individuals taking antiretroviral therapy (ART). In a two-step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared the area under the concentration-time curve from days 0 to 28 (AUC0–28 days) and the safety outcomes of piperaquine among malaria-uninfected HIV+ adults. In step 1, half the adult dose of DHA-PQ was administered for 3 days as an initial safety check to four groups (n = 6/group) of HIV+ adults (age ≥18 years): (i) antiretroviral-naive individuals, (ii) individuals on nevirapine-based ART, (iii) individuals on efavirenz-based ART, and (iv) individuals on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral-naive individuals, (ii) individuals on efavirenz-based ART, and (iii) individuals on nevirapine-based ART (n = 10 to 15/group). The ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to the limited number of participants who were on this second-line ART and were eligible for recruitment. Piperaquine's AUC0–28 days in both steps was 43% lower among participants on efavirenz-based ART than among ART-naive participants. There were no significant differences in AUC0–28 days between the other ART groups and the ART-naive group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although it was well tolerated at the half and full standard adult treatment courses, the efavirenz-based antiretroviral regimen was associated with reduced piperaquine exposure, which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings. (The clinical trials presented in this study have been registered at the WHO's International Clinical Trials Registry Platform under ID numbers PACTR2010030001871293 and PACTR2010030001971409.)
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- 2018
10. Intermittent preventive therapy in pregnancy and incidence of low birth weight in malaria-endemic countries
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Cates, Jordan E., Westreich, Daniel, Unger, Holger W., Bauserman, Melissa, Adair, Linda, Cole, Stephen R., Meshnick, Steven, Rogerson, Stephen J., Briand, V., Fievet, N., Valea, I., Tinto, H., D'Alessandro, U., Landis, S. H., Lartey, A., Dewey, K. G., TerKuile, F. O., Dellicour, S., Van Eijk, A. M., Desai, M., Owidhi, M., L'Ianziva, A., Aol, G., Were, V., Kariuki, S., Ayisi, J., Terlouw, D. J., Madanitsa, M., Mwapasa, V., Maleta, K., Ashorn, P., Mueller, I., Stanisic, D., Schmiegelow, C., Lusingu, J. P.A., Cates, Jordan E., Westreich, Daniel, Unger, Holger W., Bauserman, Melissa, Adair, Linda, Cole, Stephen R., Meshnick, Steven, Rogerson, Stephen J., Briand, V., Fievet, N., Valea, I., Tinto, H., D'Alessandro, U., Landis, S. H., Lartey, A., Dewey, K. G., TerKuile, F. O., Dellicour, S., Van Eijk, A. M., Desai, M., Owidhi, M., L'Ianziva, A., Aol, G., Were, V., Kariuki, S., Ayisi, J., Terlouw, D. J., Madanitsa, M., Mwapasa, V., Maleta, K., Ashorn, P., Mueller, I., Stanisic, D., Schmiegelow, C., and Lusingu, J. P.A.
- Abstract
Objectives. To estimate the impact of hypothetical antimalarial and nutritional interventions (which reduce the prevalence of low midupper arm circumference [MUAC]) on the incidence of low birth weight (LBW). Methods. We analyzed data from 14 633 pregnancies from 13 studies conducted across Africa and the Western Pacific from 1996 to 2015. We calculated population intervention effects for increasing intermittent preventive therapy in pregnancy (IPTp), full coverage with bed nets, reduction in malaria infection at delivery, and reductions in the prevalence of low MUAC. Results. We estimated that, compared with observed IPTp use, administering 3 or more doses of IPTp to all women would decrease the incidence of LBW from 9.9% to 6.9% (risk difference = 3.0%; 95% confidence interval = 1.7%, 4.0%). The intervention effects for eliminating malaria at delivery, increasing bed net ownership, and decreasing low MUAC prevalence were all modest. Conclusions. Increasing IPTp uptake to at least 3 doses could decrease the incidence of LBW in malaria-endemic countries. The impact of IPTp on LBW was greater than the effect of prevention of malaria, consistent with a nonmalarial effect of IPTp, measurement error, or selection bias.
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- 2018
11. Malaria, malnutrition, and adverse birth outcomes among pregnant women : a pooled analysis
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Cates, J., Unger, H. W., Briand, Valérie, Fievet, Nadine, Valea, I., Tinto, H., d'Alessandro, U., Landis, S. H., Adu-Afarwuah, S., Dewey, K. G., Ter Kuile, F., Desai, M., Dellicour, S., Ouma, P., Gutman, J., Oneko, M., Slutsker, L., Terlouw, D. J., Kariuki, S., Ayisi, J., Madanitsa, M., Kalilani-Phiri, L., Ashorn, P., Maleta, K., Mueller, I., Stanisic, D., Schmiegelow, C., Lusingu, J., van Eijk, A. M., Bauserman, M., Adair, L., Cole, S., Meshnick, S., Westreich, D., and Rogerson, S.
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- 2017
12. A new pediatric tablet strength of benznidazole for the treatment of chagas disease
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Terlouw, D. J., Alves, F. P., Sosa-Estani, S., Freilij, H., Altcheh, J., Brutus, Laurent, Kiechel, J. R., and Ribeiro, I.
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- 2009
13. Burden of malaria at community level in children less than 5 years of age in Togo
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Eliades, M. J., Wolkon, A., Morgah, K., Crawford, S. B., Monique Ameyo DORKENOO, Sodahlon, Y., Hawley, W. A., Hightower, A. W., Ter Kuile, F. O., and Terlouw, D. J.
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wa_30 ,wc_20 ,wb_710 ,wb_700 ,parasitic diseases ,wa_108 ,wa_110 ,ws_440 ,wc_750 ,ws_430 - Abstract
A community-based baseline cross-sectional survey was conducted in three districts in Togo in September 2004 as part of a multidisciplinary evaluation of the impact of the Togo National Integrated Child Health Campaign. During this campaign, long-lasting-insecticide-treated bed nets (LLITNs) were distributed to households with children between 9 months and 5 years of age throughout the country in December 2004. The pre-intervention survey provided baseline malaria and anemia prevalence in children < 5 years of age during peak malaria transmission. Of 2,532 enrolled children from 1,740 households, 62.2% (1,352/2,172) were parasitemic and 84.4% (2,129/2,524) were anemic (hemoglobin < 11 g/dL). Moderate-to-severe anemia (< 8.0 g/dL) was found in 21.7% (543/2,524), with a peak prevalence in children 6-17 months of age and was strongly correlated with parasitemia (OR = 2.3, 95% CI: 1.8-2.5). Net ownership (mainly untreated) was 225/2,532 (8.9%). Subsequent nation-wide introduction of LLITNs and the introduction of artemisinin-based combination therapy have the potential to markedly reduce this burden of malaria.
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- 2006
14. Impact of permethrin-treated bed nets on malaria, anemia, and growth in infants in an area of intense perennial malaria transmission in western Kenya
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Ter Kuile, F. O., Terlouw, D. J., Kariuki, S. K., Phillips-Howard, P. A., Mirel, L. B., Hawley, W. A., Jennifer Friedman, Shi, Y. P., Kolczak, M. S., Lal, A. A., Vulule, J. M., and Nahlen, B. L.
15. Abstracts of the 20th College of Medicine Research Dissemination Conference : Theme: College of Medicine Research Excellence Yesterday, Today, and Tomorrow
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Sande L, Chiwaula L, Kambewa P, Mathanga D, McCann R, Mburu M, Schluter D, Chipeta M, Diggle P, Terlouw D, van den Berg H, Phiri K, van Vugt M, and Maleta K
16. Impact of permethrin-treated bed nets on growth, nutritional status, and body composition of primary school children in western Kenya
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Friedman, J. F., Phillips-Howard, P. A., Hawley, W. A., Terlouw, D. J., Kolczak, M. S., Barber, M., Okello, N., Vulule, J. M., Duggan, C., Nahlen, B. L., and Feiko ter Kuile
17. Impact of permethrin-treated bed nets on malaria and all-cause morbidity in young children in an area of intense perennial malaria transmission in Western Kenya: Cross-sectional survey
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Ter Kuile, F. O., Terlouw, D. J., Phillips-Howard, P. A., Hawley, W. A., Jennifer Friedman, Kolczak, M. S., Kariuki, S. K., Shi, Y. P., Kwena, A. M., Vulule, J. M., and Nahlen, B. L.
18. Malaria and nutritional status among pre-school children: Results from cross-sectional surveys in western Kenya
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Jennifer Friedman, Kwena, A. M., Mirel, L. B., Kariuki, S. K., Terlouw, D. J., Phillips-Howard, P. A., Hawley, W. A., Nahlen, B. L., Shi, Y. P., and Ter Kuile, F. O.
19. Effects of transmission reduction by insecticide-treated bed nets (ITNs) on parasite genetics population structure: I. The genetic diversity of Plasmodium falciparum parasites by microsatellite markers in western Kenya
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Hamel Mary, Walker Edward, Lindblade Kim, Gimnig John, Nahlen Bernard, Phillips-Howard Penelope, Terlouw Dianne, ter Kuile Feiko, Hawley William, Kariuki Simon, Gatei Wangeci, Crawford Sara, Williamson John, Slutsker Laurence, and Shi Ya
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Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Insecticide-treated bed nets (ITNs) reduce malaria transmission and are an important prevention tool. However, there are still information gaps on how the reduction in malaria transmission by ITNs affects parasite genetics population structure. This study examined the relationship between transmission reduction from ITN use and the population genetic diversity of Plasmodium falciparum in an area of high ITN coverage in western Kenya. Methods Parasite genetic diversity was assessed by scoring eight single copy neutral multilocus microsatellite (MS) markers in samples collected from P. falciparum-infected children (< five years) before introduction of ITNs (1996, baseline, n = 69) and five years after intervention (2001, follow-up, n = 74). Results There were no significant changes in overall high mixed infections and unbiased expected heterozygosity between baseline (%MA = 94% and He = 0.75) and follow up (%MA = 95% and He = 0.79) years. However, locus specific analysis detected significant differences for some individual loci between the two time points. Pfg377 loci, a gametocyte-specific MS marker showed significant increase in mixed infections and He in the follow up survey (%MA = 53% and He = 0.57) compared to the baseline (%MA = 30% and He = 0.29). An opposite trend was observed in the erythrocyte binding protein (EBP) MS marker. There was moderate genetic differentiation at the Pfg377 and TAA60 loci (FST = 0.117 and 0.137 respectively) between the baseline and post-ITN parasite populations. Further analysis revealed linkage disequilibrium (LD) of the microsatellites in the baseline (14 significant pair-wise tests and ISA = 0.016) that was broken in the follow up parasite population (6 significant pairs and ISA = 0.0003). The locus specific change in He, the moderate population differentiation and break in LD between the baseline and follow up years suggest an underlying change in population sub-structure despite the stability in the overall genetic diversity and multiple infection levels. Conclusions The results from this study suggest that although P. falciparum population maintained an overall stability in genetic diversity after five years of high ITN coverage, there was significant locus specific change associated with gametocytes, marking these for further investigation.
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- 2010
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20. Impact of mass distribution of free long-lasting insecticidal nets on childhood malaria morbidity: The Togo National Integrated Child Health Campaign
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Sodahlon Yao K, Eng Jodi, Eliades M James, Dorkenoo Ameyo, Dare Aboudou, Wolkon Adam, Morgah Kodjo, Terlouw Dianne J, ter Kuile Feiko O, and Hawley William A
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Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background An evaluation of the short-term impact on childhood malaria morbidity of mass distribution of free long-lasting insecticidal nets (LLINs) to households with children aged 9-59 months as part of the Togo National Integrated Child Health Campaign. Methods The prevalence of anaemia and malaria in children aged zero to 59 months was measured during two cross-sectional household cluster-sample surveys conducted during the peak malaria transmission, three months before (Sept 2004, n = 2521) and nine months after the campaign (Sept 2005, n = 2813) in three districts representative of Togo's three epidemiological malaria transmission regions: southern tropical coastal plains (Yoto), central fertile highlands (Ogou) and northern semi-arid savannah (Tone). Results In households with children 65% in all 3 districts. Reported ITN use by children during the previous night was 35.9%, 43.8% and 80.6% in Yoto, Ogou and Tone, respectively. Rainfall patterns were comparable in both years. The overall prevalence of moderate to severe anaemia (Hb < 8.0 g/dL) was reduced by 28% (prevalence ratio [PR] 0.72, 95% CI 0.62-0.84) and mean haemoglobin was increased by 0.35 g/dL (95% CI 0.25-0.45). The effect was predominantly seen in children aged 18-59 months and in the two southern districts: PR (95% CI) for moderate to severe anaemia and clinical malaria: Yoto 0.62 (0.44-0.88) and 0.49 (0.35-0.75); Ogou 0.54 (0.37-0.79) and 0.85 (0.57-1.27), respectively. Similar reductions occurred in children Conclusions A marked reduction in childhood malaria associated morbidity was observed in the year following mass distribution of free LLINs in two of the three districts in Togo. Sub-national level impact evaluations will contribute to a better understanding of the impact of expanding national malaria control efforts.
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- 2010
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21. Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya
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Slutsker Laurence, Lal Altaf A, Terlouw Dianne, Nahlen Bernard, Kariuki Simon, ter Kuile Feiko, Crawford Sara, Eng Jodi, Prather Donald, Zhang Lyna, Udhayakumar Venkatachalam, and Shi Ya
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Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined. Methods Fifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya. Results An increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21). Conclusions This study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.
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- 2010
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22. Malaria in infants below six months of age: retrospective surveillance of hospital admission records in Blantyre, Malawi
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ter Kuile Feiko O, Molyneux Elizabeth, Larru Beatriz, Taylor Terrie, Molyneux Malcolm, and Terlouw Dianne J
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Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Information on the burden of malaria in early infancy is scarce. Young infants are relatively protected against clinical malaria during the first six months of life due to the presence of maternal antibodies and foetal haemoglobin, and have received relatively little attention with respect to research and treatment guidelines. The World Health Organization provides treatment guidelines for children from six months onwards, without specific treatment guidelines for the younger infants. A number of recent reports however suggest that the burden in this young age group may be underestimated. Methods A retrospective review of paediatric hospital records at the Queen Elizabeth Central Hospital in Blantyre from 1998 to 2008 from three data sources was carried out. The number of admitted infants Results Retrospective analysis of hospital records showed that over the course of these years, the average annual proportion of paediatric admissions in children ≤ 15 years with confirmed malaria aged Conclusions These findings are consistent with recent reports suggesting that the burden of malaria during the six first months of life may be substantial, and highlight that more research is needed on dose-optimization, safety and efficacy of anti-malarials that are currently used off-label in this vulnerable patient group.
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- 2009
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23. Paludisme : effet protecteur maximal de l'allèle HbS chez le nourrisson.
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Aldoo, M. and Terlouw, D.
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- 2002
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24. Assessing pathogenicity of mismatch repair variants of uncertain significance by molecular tumor analysis.
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van der Werf't Lam AS, Helderman NC, Boot A, Terlouw D, Morreau H, Mei H, Esveldt-van Lange REE, Lakeman IMM, van Asperen CJ, Aten E, Hofland N, de Koning Gans PAM, Rayner E, Tops C, de Wind N, van Wezel T, and Nielsen M
- Abstract
Functional analyses are the main method to classify mismatch repair (MMR) gene variants of uncertain significance (VUSs). However, the pathogenicity remains unclear for many variants because of conflicting results between clinical, molecular, and functional data. In this study, we evaluated whether whole exome sequencing (WES) could add another layer of evidence to elucidate the pathogenicity of MMR variants with conflicting interpretations. WES was performed on formalin-fixed paraffin-embedded tumor tissue of eight patients with a constitutional MMR VUS (seven families), including eight colorectal and two endometrial carcinomas and one ovarian carcinoma. Cell-free CIMRA assays were performed to assign Odds of Pathogenicity to these VUSs. In four families, seven tumors showed MMR deficiency-associated mutational signatures, supporting the pathogenicity of the VUS. Moreover, somatic (second) MMR hits identified in the WES data were found to explain MMR staining patterns when the MMR staining was discordant with the reported germline MMR gene variant. In conclusion, WES did not significantly reclassify VUS in these cases but clarified some phenotypic aspects such as age of onset and explanations in case of discordant MMR stainings., Competing Interests: Declaration of competing interest On behalf of myself and the other authors, I declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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25. PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis.
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Meuser E, Chang K, Walters A, Hurley JJ, West HD, Perry I, Mort M, Reyes-Uribe L, Truscott R, Jones N, Lawrence R, Jenkins G, Giles P, Dolwani S, Al-Sarireh B, Hawkes N, Short E, Williams GT, Taggart MW, Luetchford K, Lynch PM, Terlouw D, Nielsen M, Walton SJ, Latchford A, Clark SK, Sampson JR, Vilar E, and Thomas LE
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- Female, Humans, Male, Carcinogenesis genetics, Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli metabolism, Adenomatous Polyposis Coli pathology, Duodenal Neoplasms genetics, Duodenal Neoplasms metabolism, Duodenal Neoplasms pathology, Glycosylphosphatidylinositols metabolism, Glycosylphosphatidylinositols genetics, Membrane Proteins genetics, Membrane Proteins metabolism, Mutation
- Abstract
The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA., Implications: PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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26. MLH1 Promotor Hypermethylation in Colorectal and Endometrial Carcinomas from Patients with Lynch Syndrome.
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Helderman NC, Andini KD, van Leerdam ME, van Hest LP, Hoekman DR, Ahadova A, Bajwa-Ten Broeke SW, Bosse T, van der Logt EMJ, Imhann F, Kloor M, Langers AMJ, Smit VTHBM, Terlouw D, van Wezel T, Morreau H, and Nielsen M
- Subjects
- Female, Humans, Middle Aged, Aged, MutL Protein Homolog 1 genetics, MutL Protein Homolog 1 metabolism, Genetic Testing, Promoter Regions, Genetic, DNA Mismatch Repair genetics, Mismatch Repair Endonuclease PMS2 genetics, Mismatch Repair Endonuclease PMS2 metabolism, Germ-Line Mutation, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Endometrial Neoplasms diagnosis, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology
- Abstract
Screening for Lynch syndrome (LS) in colorectal cancer (CRC) and endometrial cancer patients generally involves immunohistochemical staining of the mismatch repair (MMR) proteins. In case of MLH1 protein loss, MLH1 promotor hypermethylation (MLH1-PM) testing is performed to indirectly distinguish the constitutional MLH1 variants from somatic epimutations. Recently, multiple studies have reported that MLH1-PM and pathogenic constitutional MMR variants are not mutually exclusive. This study describes 6 new and 86 previously reported MLH1-PM CRCs or endometrial cancers in LS patients. Of these, methylation of the MLH1 gene promotor C region was reported in 30 MLH1, 6 MSH2, 6 MSH6, and 3 PMS2 variant carriers at a median age at diagnosis of 48.5 years [interquartile range (IQR), 39-56.75 years], 39 years (IQR, 29-51 years), 58 years (IQR, 53.5-67 years), and 68 years (IQR, 65.6-68.5 years), respectively. For 31 MLH1-PM CRCs in LS patients from the literature, only the B region of the MLH1 gene promotor was tested, whereas for 13 cases in the literature the tested region was not specified. Collectively, these data indicate that a diagnosis of LS should not be excluded when MLH1-PM is detected. Clinicians should carefully consider whether follow-up genetic MMR gene testing should be offered, with age <60 to 70 years and/or a positive family history among other factors being suggestive for a potential constitutional MMR gene defect., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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27. Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients.
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Terlouw D, Boot A, Ducarmon QR, Nooij S, Suerink M, van Leerdam ME, van Egmond D, Tops CM, Zwittink RD, Ruano D, Langers AMJ, Nielsen M, van Wezel T, and Morreau H
- Subjects
- Humans, Mutation, Peptides genetics, Escherichia coli genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms microbiology, Polyketides, Adenoma genetics, Carcinoma
- Abstract
Background: Colibactin, a genotoxin produced by polyketide synthase harboring (pks
+ ) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment of pks+ Escherichia coli in colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrent APC splice variant perfectly fits SBS88., Methods: In this study, we explore the presence of colibactin-associated signatures and fecal pks in an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks., Results: NGS showed somatic APC variants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence of pks genes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without., Conclusions: These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis., (© 2024. The Author(s).)- Published
- 2024
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28. Performance of a RAD51-based functional HRD test on paraffin-embedded breast cancer tissue.
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van Wijk LM, Vermeulen S, Ter Haar NT, Kramer CJH, Terlouw D, Vrieling H, Cohen D, and Vreeswijk MPG
- Subjects
- Humans, Female, BRCA1 Protein genetics, Homologous Recombination, Paraffin Embedding, BRCA2 Protein genetics, Rad51 Recombinase genetics, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Ovarian Neoplasms genetics
- Abstract
Purpose: BRCA-deficient breast cancers (BC) are highly sensitive to platinum-based chemotherapy and PARP inhibitors due to their deficiency in the homologous recombination (HR) pathway. However, HR deficiency (HRD) extends beyond BRCA-associated BC, highlighting the need for a sensitive method to enrich for HRD tumors in an alternative way. A promising approach is the use of functional HRD tests which evaluate the HR capability of tumor cells by measuring RAD51 protein accumulation at DNA damage sites. This study aims to evaluate the performance of a functional RAD51-based HRD test for the identification of HRD BC., Methods: The functional HR status of 63 diagnostic formalin-fixed paraffin-embedded (FFPE) BC samples was determined by applying the RAD51-FFPE test. Samples were screened for the presence of (epi)genetic defects in HR and matching tumor samples were analyzed with the RECAP test, which requires ex vivo irradiated fresh tumor tissue on the premise that the HRD status as determined by the RECAP test faithfully represented the functional HR status., Results: The RAD51-FFPE test identified 23 (37%) of the tumors as HRD, including three tumors with pathogenic variants in BRCA1/2. The RAD51-FFPE test showed a sensitivity of 88% and a specificity of 76% in determining the HR-class as defined by the RECAP test., Conclusion: Given its high sensitivity and compatibility with FFPE samples, the RAD51-FFPE test holds great potential to enrich for HRD tumors, including those associated with BRCA-deficiency. This potential extends to situations where DNA-based testing may be challenging or not easily accessible in routine clinical practice. This is particularly important considering the potential implications for treatment decisions and patient stratification., (© 2023. The Author(s).)
- Published
- 2023
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29. APC mosaicism, not always isolated: two first-degree relatives with apparently distinct APC mosaicism.
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Terlouw D, Hes FJ, Suerink M, Boot A, Langers AMJ, Tops CM, van Leerdam ME, van Asperen CJ, Rozen SG, Bijlsma EK, van Wezel T, Morreau H, and Nielsen M
- Subjects
- Humans, Mosaicism, Genes, APC, Adenomatous Polyposis Coli Protein genetics, Germ-Line Mutation, Mutation, Adenomatous Polyposis Coli diagnosis, Adenomatous Polyposis Coli genetics, Colorectal Neoplasms genetics
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2023
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30. Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers.
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van der Werf-'t Lam AS, Terlouw D, Tops CM, van Kan MS, van Hest LP, Gille HJP, Duijkers FAM, Wagner A, Eikenboom EL, Letteboer TGW, de Jong MM, Bajwa-Ten Broeke SW, Bleeker FE, Gomez Garcia EB, de Wind N, van Wezel JT, Morreau H, Suerink M, and Nielsen M
- Subjects
- Female, Humans, Microsatellite Repeats, Microsatellite Instability, DNA Mismatch Repair genetics, DNA-Binding Proteins genetics, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, Colonic Neoplasms genetics, Endometrial Neoplasms genetics, Colorectal Neoplasms pathology
- Abstract
Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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31. Molecular functions of MCM8 and MCM9 and their associated pathologies.
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Helderman NC, Terlouw D, Bonjoch L, Golubicki M, Antelo M, Morreau H, van Wezel T, Castellví-Bel S, Goldberg Y, and Nielsen M
- Abstract
Minichromosome Maintenance 8 Homologous Recombination Repair Factor (MCM8) and Minichromosome Maintenance 9 Homologous Recombination Repair Factor (MCM9) are recently discovered minichromosome maintenance proteins and are implicated in multiple DNA-related processes and pathologies, including DNA replication (initiation), meiosis, homologous recombination and mismatch repair. Consistent with these molecular functions, variants of MCM8/MCM9 may predispose carriers to disorders such as infertility and cancer and should therefore be included in relevant diagnostic testing. In this overview of the (patho)physiological functions of MCM8 and MCM9 and the phenotype of MCM8/MCM9 variant carriers, we explore the potential clinical implications of MCM8/MCM9 variant carriership and highlight important future directions of MCM8 and MCM9 research. With this review, we hope to contribute to better MCM8/MCM9 variant carrier management and the potential utilization of MCM8 and MCM9 in other facets of scientific research and medical care., Competing Interests: None., (© 2023 The Author(s).)
- Published
- 2023
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32. Prevalence of mismatch repair deficiency and Lynch syndrome in a cohort of unselected small bowel adenocarcinomas.
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Suerink M, Kilinç G, Terlouw D, Hristova H, Sensuk L, van Egmond D, Farina Sarasqueta A, Langers AMJ, van Wezel T, Morreau H, and Nielsen M
- Subjects
- Aged, Cohort Studies, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, DNA Methylation genetics, DNA-Binding Proteins genetics, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mismatch Repair Endonuclease PMS2 genetics, MutL Protein Homolog 1 genetics, MutS Homolog 2 Protein genetics, Prevalence, Adenocarcinoma genetics, Adenocarcinoma pathology, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA Mismatch Repair, Intestinal Neoplasms genetics, Intestinal Neoplasms pathology
- Abstract
Aims: Previous estimates of the prevalence of mismatch repair (MMR) deficiency and Lynch syndrome in small bowel cancer have varied widely. The aim of this study was to establish the prevalence of MMR deficiency and Lynch syndrome in a large group of small bowel adenocarcinomas., Methods: To this end, a total of 400 small bowel adenocarcinomas (332 resections, 68 biopsies) were collected through the Dutch nationwide registry of histopathology and cytopathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief (PALGA)). No preselection criteria, such as family history, were applied, thus avoiding (ascertainment) bias. MMR deficiency status was determined by immunohistochemical staining of MMR proteins, supplemented by MLH1 promoter hypermethylation analysis and next generation sequencing of the MMR genes., Results: MMR deficiency was observed in 22.3% of resected and 4.4% of biopsied small bowel carcinomas. Prevalence of Lynch syndrome was 6.2% in resections and 0.0% in biopsy samples. Patients with Lynch syndrome-associated small bowel cancer were significantly younger at the time of diagnosis than patients with MMR-proficient and sporadic MMR-deficient cancers (mean age of 54.6 years vs 66.6 years and 68.8 years, respectively, p<0.000)., Conclusions: The prevalence of MMR deficiency and Lynch syndrome in resected small bowel adenocarcinomas is at least comparable to prevalence in colorectal cancers, a finding relevant both for treatment (immunotherapy) and family management. We recommend that all small bowel adenocarcinomas should be screened for MMR deficiency., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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33. The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations.
- Author
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Helderman NC, Bajwa-Ten Broeke SW, Morreau H, Suerink M, Terlouw D, van der Werf-' T Lam AS, van Wezel T, and Nielsen M
- Subjects
- DNA Mismatch Repair genetics, Germ Cells, Germ-Line Mutation, Humans, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Neoplastic Syndromes, Hereditary
- Abstract
Lynch syndrome (LS) is a hereditary cancer syndrome that accounts for 3% of all new colorectal cancer (CRC) cases. Patients carry a germline pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2), which encode proteins involved in a post-replicative proofreading and editing mechanism. The clinical presentation of LS is highly heterogeneous, showing high variability in age at onset and penetrance of cancer, which may be partly attributable to the molecular profiles of carcinomas. This review discusses the frequency of alterations in the WNT/B-CATENIN, RAF/MEK/ERK and PI3K/PTEN/AKT pathways identified in all four LS subgroups and how these changes may relate to the 'three pathway model' of carcinogenesis, in which LS CRCs develop from MMR-proficient adenomas, MMR-deficient adenomas or directly from MMR-deficient crypts. Understanding the specific differences in carcinogenesis for each LS subgroup will aid in the further optimization of guidelines for diagnosis, surveillance and treatment., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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34. Recurrent APC Splice Variant c.835-8A>G in Patients With Unexplained Colorectal Polyposis Fulfilling the Colibactin Mutational Signature.
- Author
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Terlouw D, Suerink M, Boot A, van Wezel T, Nielsen M, and Morreau H
- Subjects
- Adenoma pathology, Adenomatous Polyposis Coli pathology, Carcinoma pathology, Cohort Studies, Colorectal Neoplasms pathology, Humans, Mosaicism, Peptides, Polyketides, Adenoma genetics, Adenomatous Polyposis Coli genetics, Carcinoma genetics, Colorectal Neoplasms genetics, Genes, APC, Mutation genetics
- Published
- 2020
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35. Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy.
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Terlouw D, Suerink M, Singh SS, Gille HJJP, Hes FJ, Langers AMJ, Morreau H, Vasen HFA, Vos YJ, van Wezel T, Tops CM, Ten Broeke SW, and Nielsen M
- Subjects
- Adenomatous Polyposis Coli diagnosis, Adenomatous Polyposis Coli genetics, Adolescent, Adult, Aged, Alleles, Child, Female, Genetic Testing standards, Humans, Male, Middle Aged, Mutation, Prevalence, Adenomatous Polyposis Coli epidemiology, DNA Glycosylases genetics, Genetic Testing statistics & numerical data
- Abstract
This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged <60 and >20 adenomas aged <70. Patients with variants outside these criteria had FAP-related extracolonic manifestations, colorectal cancer aged <40, somatic KRAS c.34G > T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged <60 and with >20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing.
- Published
- 2020
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36. Supporting capacity for research on malaria in Africa.
- Author
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Greenwood B, Gaye O, Kamya MR, Kibiki G, Mwapasa V, Phiri KS, Tagbor H, Terlouw D, Bates I, Craig A, Magnussen P, Theander TG, Bhasin A, McCullough H, and Schellenberg D
- Abstract
Substantial progress has been made in the control of malaria in Africa but much remains to be done before malaria elimination on the continent can be achieved. Further progress can be made by enhancing uptake of existing control tools but, in high transmission areas, additional tools will be needed. Development and evaluation of these new tools will require a substantial cadre of African scientists well trained in many different disciplines. This paper describes the activities undertaken by the Malaria Capacity Development Consortium (MCDC) to support the careers of PhD students and postdoctoral fellows undertaking research on malaria at five African universities. A systematic assessment of constraints on PhD training and research support systems was undertaken at each partner African university at the beginning of the programme and many of these constraints were remedied. The success of the programme is shown by the fact that 18 of the 21 PhD students recruited to the programme completed their theses successfully within a 4-year period and that all 27 scientists recruited to the postdoctoral programme were still working in Africa on its completion. The work of the consortium will be continued through Career Development Groups established at each partner university and at an affiliated institution at the University of Nairobi and through the Developing Excellence in Leadership, Training and Science award from the Wellcome Trust made to one of the African partners. Lessons learnt during the MCDC programme may help the planning and execution of other research capacity development programmes in Africa., Competing Interests: Competing interests: None declared.
- Published
- 2018
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37. Uncertainties in the measurement of blood glucose in paediatric intensive care: implications for clinical trials of tight glycaemic control.
- Author
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Hill H, Baines P, Barton P, Newland P, Terlouw D, and Turner M
- Subjects
- Blood Gas Analysis, Clinical Trials as Topic, Humans, Hypoglycemic Agents administration & dosage, Insulin administration & dosage, Blood Glucose analysis, Intensive Care Units, Pediatric, Uncertainty
- Abstract
Purpose: In preparation for a tight glycaemic control (TGC) clinical trial we assessed the agreement between methods used to measure blood glucose in critically ill children., Methods: Service evaluation comparing blood gas and main laboratory analysers with point-of-care (POC) devices PCX, ACCU-Chek and Hemocue., Results: Two hundred forty-five samples from 157 children measured on 2-4 devices provided 790 values. Marked variation was evident in glucose values between devices, time between tests, sample (whole blood/plasma) and source; 39% of paired values had >20% difference. The decision to start insulin at 7 mmol/L differed depending on the device used for 33% of samples. At low glucose values (<4 mmol/L), differences up to 1.8 mmol/L were evident. The blood gas analyser read lower than all POC models and the laboratory analyser (less risk of undetected hypoglycaemia). An inverse relationship was evident between haematocrit (Hct) and glucose error using POC devices. PCX values for samples with Hct <30% were higher (85%), whereas those for Hct values >38% were lower (66%). Glycolysis occurred during transfer of samples to the laboratory. Using the PCX at the bedside resulted in 0.5 mmol/L mean difference higher than laboratory values; locating the PCX in the laboratory reduced this to 0.2 mmol/L., Conclusions: Discrepancies between measurements may mask hypoglycaemia, and the potential benefits of controlling hyperglycaemia may not be achieved. Variation introduced by different devices, sample or source may have led to misclassification of treatment decisions contributing to the conflicting results of TGC studies.
- Published
- 2011
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38. Effect of transmission reduction by insecticide-treated bednets (ITNs) on antimalarial drug resistance in western Kenya.
- Author
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Shah M, Kariuki S, Vanden Eng J, Blackstock AJ, Garner K, Gatei W, Gimnig JE, Lindblade K, Terlouw D, ter Kuile F, Hawley WA, Phillips-Howard P, Nahlen B, Walker E, Hamel MJ, Slutsker L, and Shi YP
- Subjects
- Adolescent, Adult, Child, Chloroquine therapeutic use, Drug Combinations, Female, Genotype, Humans, Kenya, Malaria, Falciparum drug therapy, Male, Membrane Transport Proteins genetics, Multidrug Resistance-Associated Proteins genetics, Multivariate Analysis, Mutation, Plasmodium falciparum drug effects, Plasmodium falciparum genetics, Polymorphism, Single Nucleotide genetics, Protozoan Proteins genetics, Pyrimethamine therapeutic use, Sulfadoxine therapeutic use, Young Adult, Antimalarials therapeutic use, Drug Resistance genetics, Insecticide-Treated Bednets, Malaria, Falciparum transmission
- Abstract
Despite the clear public health benefit of insecticide-treated bednets (ITNs), the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250) and five years post-ITN intervention (year 5 survey, n = 242) were genotyped for single nucleotide polymorphisms (SNPs) at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance), and pfcrt-76 and pfmdr1-86 (CQ resistance). The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria drug resistance.
- Published
- 2011
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39. Effects of transmission reduction by insecticide-treated bed nets (ITNs) on parasite genetics population structure: I. The genetic diversity of Plasmodium falciparum parasites by microsatellite markers in western Kenya.
- Author
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Gatei W, Kariuki S, Hawley W, ter Kuile F, Terlouw D, Phillips-Howard P, Nahlen B, Gimnig J, Lindblade K, Walker E, Hamel M, Crawford S, Williamson J, Slutsker L, and Shi YP
- Subjects
- Child, Preschool, Humans, Infant, Infant, Newborn, Kenya, Malaria, Falciparum transmission, Microsatellite Repeats, Plasmodium falciparum isolation & purification, Genetic Variation, Insecticide-Treated Bednets, Malaria, Falciparum parasitology, Malaria, Falciparum prevention & control, Mosquito Control methods, Plasmodium falciparum classification, Plasmodium falciparum genetics
- Abstract
Background: Insecticide-treated bed nets (ITNs) reduce malaria transmission and are an important prevention tool. However, there are still information gaps on how the reduction in malaria transmission by ITNs affects parasite genetics population structure. This study examined the relationship between transmission reduction from ITN use and the population genetic diversity of Plasmodium falciparum in an area of high ITN coverage in western Kenya., Methods: Parasite genetic diversity was assessed by scoring eight single copy neutral multilocus microsatellite (MS) markers in samples collected from P. falciparum-infected children (< five years) before introduction of ITNs (1996, baseline, n = 69) and five years after intervention (2001, follow-up, n = 74)., Results: There were no significant changes in overall high mixed infections and unbiased expected heterozygosity between baseline (%MA = 94% and He = 0.75) and follow up (%MA = 95% and He = 0.79) years. However, locus specific analysis detected significant differences for some individual loci between the two time points. Pfg377 loci, a gametocyte-specific MS marker showed significant increase in mixed infections and He in the follow up survey (%MA = 53% and He = 0.57) compared to the baseline (%MA = 30% and He = 0.29). An opposite trend was observed in the erythrocyte binding protein (EBP) MS marker. There was moderate genetic differentiation at the Pfg377 and TAA60 loci (FST = 0.117 and 0.137 respectively) between the baseline and post-ITN parasite populations. Further analysis revealed linkage disequilibrium (LD) of the microsatellites in the baseline (14 significant pair-wise tests and ISA = 0.016) that was broken in the follow up parasite population (6 significant pairs and ISA = 0.0003). The locus specific change in He, the moderate population differentiation and break in LD between the baseline and follow up years suggest an underlying change in population sub-structure despite the stability in the overall genetic diversity and multiple infection levels., Conclusions: The results from this study suggest that although P. falciparum population maintained an overall stability in genetic diversity after five years of high ITN coverage, there was significant locus specific change associated with gametocytes, marking these for further investigation.
- Published
- 2010
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40. Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya.
- Author
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Zhang L, Prather D, Vanden Eng J, Crawford S, Kariuki S, ter Kuile F, Terlouw D, Nahlen B, Lal AA, Slutsker L, Udhayakumar V, and Shi YP
- Subjects
- Anemia etiology, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Humans, Infant, Infant, Newborn, Kenya, Malaria complications, Male, Phenotype, Polymorphism, Single Nucleotide, Anemia genetics, Interleukin-12 Subunit p35 genetics, Malaria genetics, Plasmodium falciparum isolation & purification, Receptors, Interleukin-12 genetics
- Abstract
Background: Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined., Methods: Fifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya., Results: An increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21)., Conclusions: This study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.
- Published
- 2010
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41. Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX.
- Author
-
Aidoo M, McElroy PD, Kolczak MS, Terlouw DJ, ter Kuile FO, Nahlen B, Lal AA, and Udhayakumar V
- Subjects
- Alleles, Female, Genotype, Humans, Infant, Newborn, Infant, Premature, Kenya epidemiology, Malaria, Falciparum epidemiology, Male, Poisson Distribution, Polymorphism, Genetic, Pregnancy, Proportional Hazards Models, Retrospective Studies, Risk Factors, Survival Analysis, Genetic Predisposition to Disease, Infant Mortality, Malaria, Falciparum genetics, Obstetric Labor, Premature genetics, Promoter Regions, Genetic, Tumor Necrosis Factor-alpha genetics
- Abstract
A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene, with a guanine to adenine nucleotide change at position -308, TNF2 is associated with increased TNF-alpha production. TNF2 homozygotes have a higher risk of severe disease and/or death due to cerebral malaria and other infectious diseases. We investigated the impact of this allele on malaria morbidity and mortality in young children who participated in an immuno-epidemiologic cohort study of malaria in an area of intense perennial Plasmodium falciparum transmission in western Kenya. A total of 1,048 children were genotyped. Poisson regression and Cox proportional hazards models were used to determine the relationship between TNF-308 variants and morbidity and mortality. The gene frequencies of the TNF1 and TNF2 alleles were 0.90 and 0.10, respectively. TNF2 homozygosity was associated with pre-term birth when compared with TNF1 homozygotes [relative risk (RR) 7.3, 95% CI, 2.85-18.9, P = 0.002) and heterozygotes (RR 6.7, 95% CI 2.0-23.0, P = 0.008). Among children born prematurely, the TNF2 allele was significantly associated with a higher risk of death in infancy compared with TNF1 (RR 7.47, 95% CI 2.36-23.6). The risk of death was higher among TNF2 homozygotes than among heterozygotes. The TNF2 allele was significantly associated with high density P. falciparum parasitemia (RR 1.11, 95% CI 1.0-1.24). Among low birth weight children, the TNF2 allele was associated with severe anemia (RR 2.16, 95% CI 1.17-4.01) and showed a trend toward a risk for severe malaria anemia (RR 1.99, 95% CI 0.89-4.46). These data suggest that TNF2 is a risk factor for pre-term birth and early childhood mortality and malaria morbidity in children in this region. Further understanding of the pathogenic mechanisms underlying this association is required., (Copyright 2001 Wiley-Liss, Inc.)
- Published
- 2001
- Full Text
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