Journal/Magazine Articles
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This collection contains original research articles, review articles and case reports published in local and international peer reviewed journals by the staff members of the Faculty of Medicine
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Item Human resources for health in Sri Lanka over the post-independence period: key issues(Sri Lanka Medical Association, 2023) de Silva, D.; Chandratilake, M.; de Silva, N.No abstract availableItem Correction:Arterial tortuosity syndrome: 40 new families and literature review(Nature Publishing Group, 2019) Beyens, A.; Albuisson, J.; Boel, A.; Al-Essa, M.; Al-Manea, W.; Bonnet, D.; Bostan, O.; Boute, O.; Busa, T.; Chanham, N.; Cil, E.; Couke, P.J.; Cousin, M.A.; Dasouki, M.; Da Backer, J.; De Paepe, A.; de Schepper, S.; de Silva, D.; Devriendt, K.; De Wandele, I.; Deyle, D.R.; Dietz, H.; Dupuis-Giroid, S.; Fontenot, E.; Fischer-Zirnsak, B.; Gezdirici, A.; Ghoumid, J.; Giuliano, F.; Baena, N.; Haider, M.Z.; Hardin, J.S.; Jeunemaitre, X.; Klee, E.W.; Kornak, U.; Landecho, M.F.; Legrand, A.; Loeys, B.; Lyonnet, S.; Michael, H.; Moceri, P.; Mohammed, S.; Muino-Mosquera, L.; Nampoothiri, S.; Picher, K.; Prescott, K.; Rajeb, A.; Ramos-Arroyo, M.; Rossi, M.; Salih, M.; Seidahmed, M.Z.; Schaefer, E.; Steichen-Gersdorf, E.; Temel, S.; Uysal, F.; Vanhomwegen, M.; Van Laer, L.; Van Maldergem, L.; Warner, D.; Willaert, A.; Collins, T.R.; Taylor, A.; Davis, E.C.; Zarate, Y.; Callewaert, B.In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper. Erratum for:Arterial tortuosity syndrome: 40 new families and literature review. Beyens A. et al. [Genet Med. 2018;20(10):1236-1245. doi: 10.1038/gim.2017.253] .Item Arterial tortuosity syndrome: 40 new families and literature review(Nature Publishing Group, 2018) Beyens, A.; Albuisson, J.; Boel, A.; Al-Essa, M.; Al-Manea, W.; Bonnet, D.; Bostan, O.; Boute, O.; Busa, T.; Chanham, ,N.; Cil, E.; Couke, P.J.; Cousin, M.A.; Dasouki, M.; Da Backer, J.; De Paepe, A.; de Schepper, S.; de Silva, D.; Devriendt, K.; De Wandele, I.; Deyle, D.R.; Dietz, H.; Dupuis-Giroid, S.; Fontenot, E.; Fischer-Zirnsak, B.; Gezdirici, A.; Ghoumid, J.; Giuliano, F.; Baena, N; Haider, M.Z.; Hardin, J.S.; Jeunemaitre, X.; Klee, E.W.; Kornak, U.; Landecho, M.F.; Legrand, A.; Loeys, B.; Lyonnet, S.; Michael, H.; Moceri, P.; Mohammed, S.; Muino-Mosquera, L.; Nampoothiri, S.; Picher, K.; Prescott, k.; Rajeb, A.; Ramos-Arroyo, M.; Rossi, M.; Salih, M.; Seidahmed, M.Z.; Schaefer, E.; Steichen-Gersdorf, E.; Temel, S.; Uysal, F.; Vanhomwegen, M.; Van Laer, L.; Van Maldergem, L.; Warner, D.; Willaert, A.; Collins, T.R.; Taylor, A.; Davis, E.C.; Zarate, Y.; Callewaert, B.PurposeWe delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.MethodsWe retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.ResultsStenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.ConclusionOur findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities. In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.(Baena N)Genetics in Medicine 2018; Sep 10Item Noncoding copy-number variations are associated with congenital limb malformation(Nature Publishing Group, 2018) Flöttmann, R.; Kragesteen, B.K.; Geuer, S.; Socha, M.; Allou, L.; Sowińska-Seidler, A.; Bosquillon de Jarcy, L.; Wagner, J.; Jamsheer, A.; Oehl-Jaschkowitz, B.; Wittler, L.; de Silva, D.; Kurth, I.; Maya, I.; Santos-Simarro, F.; Hülsemann, W.; Klopocki, E.; Mountford, R.; Fryer, A.; Borck, G.; Horn, D.; Lapunzina, P.; Wilson, M.; Mascrez, B.; Duboule, D.; Mundlos, S.; Spielmann, M.PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.Conclusion:Our findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations.Item Mutations in CDC45, encoding an essential component of the Pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis(University of Chicago Press, 2016) Fenwick, A.L.; Kliszczak, M.; Cooper, F.; Murray, J.; Sanchez-Pulido, L.; Twigg, S.R.; Goriely, A.; McGowan, S.J.; Miller, K.A.; Taylor, I.B.; Logan, C.; Bozdogan, S.; Danda, S.; Dixon, J.; Elsayed, S.M.; Elsobky, E.; Gardham, A.; Hoffer, M.J.; Koopmans, M.; McDonald-McGinn, D.M.; Santen, G.W.; Savarirayan, R.; de Silva, D.; Vanakker, O.; Wall, S.A.; Wilson, L.C.; Yuregir, O.O.; Zackai, E.H.; Ponting, C.P.; Jackson, A.P.; Wilkie, A.; Niedzwiedz, W.; Bicknell, L.S.DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis.Item Mutations in ANTXR1 cause GAPO syndrome(University of Chicago Press, 2013) Stránecký, V.; Hoischen, A.; Hartmannová, H.; Zaki, M.S.; Chaudhary, A.; Zudaire, E.; Nosková, L.; Barešová, V.; Přistoupilová, A.; Hodaňová, K.; Sovová, J.; Hůlková, H.; Piherová, L.; Hehir-Kwa, J.Y.; de Silva, D.; Senanayake, M.P.; Farrag, S.; Zeman, J.; Martásek, P.; Baxová, A.; Afifi, H.H.; St Croix, B.; Brunner, H.G.; Temtamy, S.; Kmoch, S.The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsensemutations (c.262C>T [p.Arg88*] and c.505C>T [p.Arg169*]) or splicing mutations (c.1435-12A>G [p.Gly479Phefs*119]) in ANTXR1, which encodes anthrax toxin receptor 1. The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss ofANTXR1. The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus. GAPO syndrome's major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation. Thus, we propose that mutations affecting ANTXR1 function are responsible for this disease's characteristic generalized defect in extracellular-matrix homeostasisItem Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2(Wiley, 2013) Bornholdt, D.; Atkinson, T.P.; Bouadjar, B.; Catteau, B.; Cox, H.; de Silva, D.; Fischer, J.; Gunasekera, C.N.; Hadj-Rabia, S.; Happle, R.; Holder-Espinasse, M.; Kaminski, E.; Konig, A.; Megarbane, A.; Megarbane, H.; Neidel, U.; Oeffner, F.; Oji, V.; Theos, A.; Traupe, H.; Vahlquist, A.; van Bon, B.W.; Virtanen, M.; Grzeschik, K.H.Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missensemutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component. © 2013 Wiley Periodicals, Inc.Item Community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol(BioMed Central, 2011) Pearson, M.; Konradsen, F.; Gunnell, D.; Dawson, A.H.; Pieris, R.; Weerasinghe, M.; Knipe, D.W.; Jayamanne, S.; Metcalfe, C.; Hawton, K.; Wickremasinghe, A.R.; Atapattu, W.; Bandara, P.; de Silva, D.; Ranasinghe, A.; Mohamed, F.; Buckley, N.A.; Gawarammana, I.; Eddleston, M.A.BACKGROUND: The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. METHODS/DESIGN: A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. DISCUSSION: This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence.Item A Comparison of the cytotoxic potential of standardized aqueous and ethanolic extracts of a polyherbal mixture comprised of Nigella sativa (seeds), Hemidesmus indicus (roots) and Smilax glabra (rhizome)(Medknow Publications, 2010) Samarakoon, S.R.; Thabrew, I.; Galhena, P.B.; de Silva, D.; Tennekoon, K.H.BACKGROUND: A decoction (hot-water extract) comprised of Nigella sativa (seeds), Hemidesmus indicus (roots), and Smilax glabra (rhizome) has been reported to prevent chemically-induced hepatocarcinogenic changes in rats and to exert significant cytotoxic effects on human hepatoma (HepG2) cells. However, the decoction used in previous studies to determine cytotoxicity was not standardized. Further, during preparation of pharmaceuticals for clinical use, it is more convenient to use an ethanolic extract. Therefore this study was carried out to (a) develop standardizedaqueous and ethanolic extracts of the plant mixture (N. sativa, H. indicus, and S. glabra) used in the preparation of the original decoction, and (b) compare the cytotoxic effects of these two extracts by evaluating cytotoxicity to the human hepatoma (HepG2) cell line. METHODS: Aqueous and ethanolic extracts have been standardized by evaluating organoleptic characters, physicochemical properties, qualitative and quantitative analysis of chemical constituents, and analysis of High Performance Liquid Chromatography (HPLC) and Thin Layer Chromatography (TLC) profiles. Cytotoxic potentials of the above standardized extracts were compared by evaluating their effects on the survival and overall cell activity of HepG2 cells by use of the 3-(4, 5-dimethylthiazol-2yl) -2, 5 - biphenyl tetrazolium bromide (MTT) and Sulphorhodamine B (SRB) assays. RESULTS: Results from MTT and SRB assays demonstrated that both extracts exerted strong dose-dependent in vitro cytotoxicity to HepG2 cells. The standardized aqueous extract showed a marginally (though significantly, P<0.05) higher cyotoxic potential than the ethanolic extract. Thymoquinone, an already known cytotoxic compound isolated from N. sativa seeds was only observed in the standardized ethanolic extract. Thus, compounds other than thymoquinone appear to mediate the cytotoxicity of the standardized aqueous extract of this poly-herbal preparation. CONCLUSION: It may be concluded that results obtained in the present study could be used as a diagnostic tool for the correct identification of these aqueous or ethanolic extracts and would be useful for the preparation of a standardized pharmaceutical product that may be used in the future for clinical therapy of hepatocellular carcinoma.Item Hartsfield holoprosencephaly-ectrodactyly syndrome in five male patients: further delineation and review(Wiley-Blackwell, 2009) Vilain, C.; Mortier, G.; Van, G. V.; Dubourg, C.; Heinrichs, C.; de Silva, D.; Verloes, C. B.We report on five male subjects with a triad of signs compatible with Hartsfield syndrome: ectrodactyly, holoprosencephaly, and mental retardation. Only six patients with this distinctive association have been reported over the past 20 years, all of them being males. Of the patients described here, some have unreported findings such as vermian hypoplasia in one and prolonged survival into adulthood in two. Two patients developed central diabetes insipidus. All were mentally retarded. No abnormalities were found at the cytogenetic level, including array CGH in two. No known genes for holoprosencephaly or ectrodactyly were found, including GLI2. The cause of Hartsfield syndrome is unknown. An X-linked defect is possible, although no recurrences have been described to date. Our observations almost double the number of cases. They underscore the usefulness of fetal brain imaging in the differential diagnosis of syndromal clefting diagnosed in utero, particularly when ectrodactyly-ectodermal dysplasia-clefting syndrome is suspected.
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