Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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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 Heart rate variability among gas station attendants exposed to benzene, toluene, and xylenes (BTX) in Sri Lanka(Springer Nature., 2021) Warnakulasuriya, T.; Medagoda, K.; Kottahachchi, D.; Luke, D.; Wadasinghe, D.; de Silva, D.; Ariyawansha, J.; Rathnayaka, P.; Dissanayaka, T.; Fernando, S.; Devanarayana, N.M.; Scheepers, P.T.J.Introduction: Benzene, toluene, and xylenes (BTX) exposure among gas station attendants in Sri Lanka is high. Cardiovascular morbidity and mortality are reported to be higher among those exposed to BTX. A hypothesis is based on alterations in the autonomic nervous system, especially disruption of autonomic regulation of the heart. Autonomic regulation of cardiac functions can be assessed by short-term heart rate variability (HRV), which measures the fluctuations in the interval between sequential sinus heartbeats. Objective: To determine whether BTX exposure affects the heart rate variability (HRV) among gas station attendants. Methods: Forty-nine gas station attendants from the Gampaha district of Sri Lanka, aged between 19 and 65 years, were recruited for the study. Age and gender-matched controls (n = 46) without occupational exposure to fuel were used as controls. Ethical approval for the study was granted by the Ethics Review Committee of the Faculty of Medicine, University of Kelaniya, Sri Lanka. Informed written consent was obtained from each participant. Demographic data were collected, and a physical examination was performed before the HRV assessment. We measured SDNN, RMSSD, pNN50, HF, LF, and LF: HF ratio as HRV indices. Pre- and post-shift samples of end-exhaled air were collected and analyzed for BTX using a thermal desorption gas chromatography–mass spectrometry system (TD-GC-MS) among 24 gas station attendants and 14 controls. As a proxy of shift exposure, we calculated the increase from pre-shift (as a baseline) to postshift and reported this as ‘delta’. Results and discussion: For gas station attendants (n = 24) median pre-/post-shift exhaled air concentrations (ng/L) were: benzene 10.47/ 19.00; toluene 10.41/21.86; m/p-xylene 1.63/2.14; o-xylene 0.93/1.42. For controls (n = 14) these values were 9.40/11.05, 3.19/3.91, 1.23/ 1.43 and 0.47/0.47. The heart rate variability (HRV) analysis showed significantly higher SDNN and SD2 among the gas station attendants (n = 49) than controls (n = 46) (Mann Whitney U = 842.00, p = 0.034 and Mann Whitney U = 843.50, p = 0.035, respectively). RMSSD, pNN50, Total power, HF, and SD1 among gas station attendants negatively correlated at a significant level with the mean increment in exposure to BTX (p\0.05).Conclusions: Exposure to BTX alters the HRV indices, indicating an effect on autonomic cardiac regulation. Funding: University of Kelaniya research grant: RP/03/04/03/01/ 2017, Foreign Award 2017 of the Dutch Occupational Hygiene Society (NVvA).Item Cardiovascular autonomic functions of gas station attendants in Sri Lanka(Springer Nature., 2021) Warnakulasuriya, T.; Medagoda, K.; Kottahachchi, D.; Luke, D.; Wadasinghe, D.; de Silva, D.; Ariyawansha, J.; Rathnayaka, P.; Dissanayaka, T.; Fernando, S.; Devanarayana, N.M.Introduction: Sri Lanka, a middle-income country in South Asia, has seen a rapid expansion in motor vehicles and, associated with this, an increase in demand for fuel. The dispensing of fuel at fuel stations is performed manually by male fuel handlers, who have long working hours. Such workers are exposed to hydrocarbon fuels which are associated with multiple health effects. This study was performed to determine cardiovascular autonomic functions among fuel handlers in a densely populated district of Sri Lanka. Methods: Fuel handlers (n = 50) from the Gampaha district of Sri Lanka, aged between 19 and 65 years, were identified for the study from seven selected fuel stations. Age and gender-matched controls (n = 46) without occupational exposure to fuel were used as controls. All participants were male (females were not employed as fuel handlers). After obtaining written informed consent, demographic data were collected, and general physical examination performed before autonomic function assessment. Non-parametric methods were used for data analysis. Ethical approval was granted by the ethics review committee of the Faculty of Medicine, University of Kelaniya, Sri Lanka. Results: There were no significant differences in weight, height or BMI among the study and the control populations (p[0.05). Both the systolic (SBP) and diastolic (DBP) blood pressures were significantly higher among the fuel handlers compared to controls (SBP, Mann Whitney U = 743.5, p = 0.003) and (DBP, Mann Whitney U = 686.5, p = 0.001). Valsalva ratio was significantly higher among the fuel handlers (Mann Whitney U—874.00, p = 0.043). The rise in DBP during sustained handgrip, a sympathetic parameter, was significantly higher among the controls (Mann Whitney U = 863.00, p = 0.049). Conclusions: Altered sympathetic:parasympathetic balance was observed among the fuel handlers. Monitoring of the health, using personal protective equipment, and curtailing hours of employment per week is recommended for those employed at fuel stations.Item 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 A Unique syndrome with facial, cranial, dental and skeletal features: possible relationship to maternal chikungunya exposure or an unidentified genetic cause?(Sri Lanka College of Paediatricians, 2015) de Silva, D.; Basnayake, S.; Gunasekara, R.; Smith, J. C.; Donnai, D.; Newman, B.BACKGROUND:Six children from the western province of Sri Lanka, born between June 2007 and November 2008 have presented with a unique phenotype comprising distinctive facial features, skeletal abnormalities and variable intellectual disability. In four children the mother reported a clinical history of chikungunya infection (CHKV) during their first trimester. OBJECTIVE: • Describe the clinical and demographic features of affected cases • Identify a genetic basis using whole exome sequencing (WES) DESIGN, SETTING AND METHOD: Cases were recruited following informed consent from parents. Blood taken for DNA extraction and WES performed using the lllumina HiSeq 2500 platform. Reads were aligned to the human reference sequence hg19 and analysed using bioinformatics software. RESULTS: Four cases were females. Five were Sinhalese, one Tamil. None had parental consanguinity. Four mothers reported first trimester CHKV infection. Distinctive facial features (pinched face, downslanting eyes, turri-brachvcephalv, open mouth, lip retraction, V shaped dental arches and high mandibular angles), restriction of joint movements (small and large joints) and variable developmental delay were present. Review by a panel of experts revealed no syndrome diagnosis WES analysis on five cases did not identify a homozygous or compound heterozygous recessive or de novo dominant mutation of an autosomal gene. CONCLUSIONS: WES analysis did not identify a homozygous or compound heterozygous recessive or de novo dominant mutation of an autosomal gene.Item Molecular diagnosis of velo-cardio-facial syndrome among sri lankan patients with congenital cardiac defects(Sri Lanka College of Paediatricians, 2015) Tevarajan, I.; Ranaweera, D. M.; Perera, S.; Samarasinghe, D.; Morawakkorala, R.; Silva, R. L.; de Silva, D.; Chandrasekharan, N.V.Velo cardio facial Syndrome (VCFS) is caused by a 3 Mb deletion of chromosome 22qll.2. Its multiple clinical features include orofacial clefting, congenital cardiac defects (especially conotruncal),developmental delay and learning difficulties. Hypoparathyroidism and thymic hypoplasia are associated. Dysmorphic features include expressionless face, prominent nose, narrow eyes and long fingers/ toes. Clinical diagnosis is difficult due to its variability making molecular diagnosis essential but this is often too expensive for widespread use. We have developed a less expensive semi-quantitative PCR method for diagnosing VCFS and report preliminary results in congenital cardiac defect patients.OBJECTIVE: • Identify the 22qll.2 deletion syndrome among a selected group of children with typical cardiac defects • Describe clinical features of affected cases DESIGN, SETTING AND METHOD: TweIve children (6 males, mean age 3y lmo) with conotruncal congenital cardiac anomalies or cardiac defects associated with other clinical feature of VCFS were .recruited following informed consent from parents. Ethical approval had been granted for this study. A blood sample was obtained for DNA extraction and the clinical data recorded. Molecular diagnosis was performed using semi-quantitative PCR. RESULTS: Three cases were positive for the deletion. Their cardiac anomalies were an interrupted aortic arch,tetralogy of Fallot and right sided aortic arch. None had palatal anomalies and two (67%) had learning difficulties. None had a positive family history. Only one had facies that were typical. The negative cases included six with aortic arch anomalies, none with clefting and 4 with learning difficulties(44). Two had a family history suggestive of VCFS and two had typical facial features. CONCLUSIONS: Three out of the 12 children were positive for the 22qll.2 deletion.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 Molecular diagnosis of Williams Buren syndrome in a cohort of Sri Lankan patients(Sri Lanka Medical Association, 2012) Ranaweera, D.M.; de Silva, D.; Samarasinghe, D.; Perera, S.; Rajapaksha, N.; Chandrasekharan, N.V.INTRODUCTION: Williams Bueren Syndrome (WBS) is a common genetic cause of congenital heart defects associated with developmental delay, hypercalcaemia and characteristic facial dysmorphism. It is caused by a 1.5 to 1.8 Mb deletion of chromosome 7qll.23 involving the loss of around 23 genes including the elastin (ELN) gene. This study reports the development of a semi quantitative PCR method to diagnose WBS. AIMS: To establish a molecular diagnostic test for WBS and determine the frequency of ELN deletions among clinically suspected cases. METHODS: Sixteen suspected WBS cases identified by two paediatric cardiologists were recruited following ethical clearance and informed consent. DNA was extracted and dosage analysis was carried out using semi-quantitative PCR. In a multiplex PCR reaction normal (N), positive control (with a confirmed deletion) and patients' (PJ DNA was amplified using 2 primer pairs which amplified regions within the ELN gene and the CFTR gene on chromosome 7 but outside the deleted region. Following agarose gel electrophoresis, the amplified products were quantified. A ratio of P:N of 0.5 indicated the presence of a deletion while a ratio of 1 indicated the absence of a deletion. RESULTS: Among sixteen suspected cases, 12 (75%) had an ELN gene deletion while 4 cases did not. CONCLUSIONS: This semi-quantitative PCR method was able to distinguish ELN deleted cases from the non deleted ones. The preliminary data supports this as a useful diagnostic test for WBS but validation is required before its clinical use.
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