Theses - Faculty of Medicine
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Item The ileocaecal valve-functional morphology, blood supply and pressure charasteristics in humans(University of Kelaniya, 2009) Fernando, E.D.P.S.INTRODUCTION: The function of the ileocaecal valve still remains controversial, especially the importance of preservation of the valve during right hemicolectomy. This research was carried-out with an objective to study manometric characteristics combined with videography and the neuronal density to assess the capability of this structure to function as a sphincter. A detailed study of the arterial supply of the ileocaecal region was also done with a view of exploring the possibility of a modified right-hemicolectomy with a preserved ileocaecal valve with adequate arterial blood supply to the anastomosis. PATIENTS AND METHOD - The ganglion density of the ileocaecal region was studied in 73 cadavers within 12 hours of death using haematoxylin and eosin staining. The manometry of the ileocaecal region was studied using a water-filled balloon catheter in twenty-one individuals who underwent colonoscopy. Mean intra-luminal pressure (area under the curve/ duration) was also measured during this procedure. Further more, valve videography was performed in thirteen individuals. Fifty-four fresh human cadavers were studied with informed written consent from relatives. In this study, 20cm of terminal ileum with the ileocaecal segment and approximately 20cm of ascending colon were removed en-block with its mesentery and blood supply. The ileocolic artery was cannulated and injected with 10ml of water-soluble red-dye under pressure. The arterial supply was dissected to demonstrate a pattern. RESULTS: Study on density of the ganglia of myenteric plexus in the ileocaecal region Of 73 specimens studied, the ileocaecal valve had the highest number of ganglions found in one mm of area (mean 0.491 ganglions/mm ; SD 0.283). The terminal ileum had a mean of 0.322 ganglions/mm2; SD 0.209. The least number of ganglia was found in the caecal sections (mean 0.241 ganglions/mm ; SD 0.166). These findings showed a statistically significant (P<0.0001) higher number of ganglions per mm2 in the ileocaecal valve (ICV) than in the terminal ileum or caecum. Study of the pressure gradient across the ileocaecal valve in normal adults: In twenty individuals (95%), the intra-ileal pressure exceeded the intra-caecal pressure {ileal pressure [mean 4018.77, S.D. 4386.51] Pa vs. caecal pressure [mean 1742.64, S.D 4537.54] Pa}, P<0.001. Ante-grade pressure gradients were observed from terminal ileum to caecum in fifteen participants (71%). In five (24%), a high-pressure zone was observed within the ileocaecal valve. A reverse gradient was seen in one (5%). Study of the ileocaecal valve cusp movements in live normal adults using video ecordings during colonoscopy: Videography of the ileocaecal valve was analyzed in thirteen subjects for a total of 121 minutes (mean 9.3 minutes per subject). The valve orifice was observed to be at rest during alternating periods of contraction. Contractions of the valve cusps seemed to change the shape of its orifice. In 11 subjects, during the resting period of the valve, the orifice was semilunar and either closed or partially closed. These subjects had a longer and more curved superior cusp. The valve cusps were thickened in six subjects, while seven had narrow valve cusps. In all, 60 (mean — 5 per subject) active movements were observed in the ileocaecal valve cusps with 14 active caecal contractions. The frequency of active movements of the valve was 0.5 movements per minute. The ejection of effluent was observed on 49 occasions (mean - 4 ejections per XV subject). Chyme was ejected in 15 instances and air in 34 instances. The ejection of effluent was always associated with active movements of the valve cusps. By contrast, some cusp movements were observed to be independent of the onward flow of effluent. Caecal wall contractions were found to be less frequent and were observed on 14 occasions. Study of the arterial supply of the ileocaecal region: In fifty-six cadaveric specimens, the ICV was supplied by the ileocolic artery, a branch of the superior mesenteric, which divided into an anterior and a posterior caecal artery. A marginal branch of the right colic was noted to contribute to the ICV blood supply in only two (4%). Furthermore, study of the anastomosis at the ICV showed that the anterior caecal artery was present in all (100%), posterior caecal in 48(89%) and recurrent ileal artery present in fifty-three (98%). A rich anastomosis between vessels at the ICV: small 'windows', short tributaries, was seen in thirty-eight (70%) whilst a poor anastomotic network at the ICV: large 'windows', long tributaries, between these vessels was seen in twelve (22%). In four (8%), we were unable to determine clearly between rich and poor anastomotic networks. Other variants included an absent posterior caecal artery in six (11%) and absent recurrent ileal artery in one (2%). CONCLUSIONS: Manometry of the ileocaecal valve revealed a flap valve with an ante-grade pressure gradient in the majority. A reverse pressure gradient may explain valve incompetence. The ileocaecal valve had a predictable blood supply in the majority of patients. Preservation of the anterior caecal artery would ensure a vascularized ileocaecal valve in right hemicolectomy.Item Effects of zinc on human semen quality and sexual behaviour of male rats(University of Kelaniya, 2008) Dissanayake, D.M.A.B.The main aim of this study was to evaluate the effects of serum and seminal plasma zinc levels on semen quality of a subfertile male population. At the same time, effects of zinc on different aspects of male reproduction were studied. The study was carried out as a prospective hospital and laboratory based study. Semen samples from 152 males were analyzed. Seminal plasma and serum levels of zinc, serum hormone levels, seminal plasma fructose and neutral a- glucosidase levels of same males were also measured. Relationship between seminal plasma zinc and semen quality was observed using two markers; zinc concentration and total zinc per ejaculate (Total zinc). Effects of zinc on various functions of spermatozoa were studied in-vitro and, the effects on sexual competence of males were observed using a rat model. Of the 152 semen samples 55 (36 %) were normozoospermic and 97 (64 %) were pathozoospermic. The mean (SD) serum and seminal plasma zinc concentrations of the population were 0.94 (ig/ml (0.36) and 121.87 (ig/ml (69.13) respectively. Seminal plasma total zinc was significantly low in samples with low volume and hyperviscosity compared to samples with normal volume and viscosity; 139.72 ]ig (73.72) vs. 377.40 (ig (231.06), p < 0.01 for volume and 220.06 jag (144.09) vs. 336.34 |Ag (236.33), p < 0.05 for viscosity. Conversely significantly high amount of total zinc was found in low viability group compared to normal; 437.67 ug (283.88) vs. 305.15 (ig (221.19), p < 0.05. Percentage of pathozoospermics and volume abnormalities were significantly higher in abnormal total seminal zinc group compared to normal (pathozoospermics, 27 % vs. 7.3 % and volume abnormalities, 55.3 % vs. 8.8 %, p < 0.05). Mean zinc concentratiorfwas significantly high in Asthenozoospermics compared to normal motile group; 138.11 u.g/ml (83.92) vs. 110.69 11 fig/ml (54.59), p < 0.05. Significantly positive correlations were found between total seminal plasma zinc and volume (r = 0.53, p < 0.01) as well as total sperm count (r = 0.21, p < 0.05). whereas correlation between seminal zinc and pH was inverse (r = -0,193, p < 0.05 for zinc concentration and r = -0.280, p < 0.01 for total zinc). In contrast serum zinc levels correlated positively with seminal plasma pH (r = 0.167, p < 0.05). Gonadotropin levels were significantly high in azoospermics compared to normozoospennics; LH - 12.82 mlU/ml (11.82) vs. 5.90 mlU/ml (2.78), FSH - 19.69 mlU/ml (9.93) vs. 4.18 mlU/ml (2.78), p < 0.05). FSH level was inversely correlated with sperm concentration (r = -0.203, p < 0.05) and total sperm count (r = -0.206, p < 0.05). There was an inverse correlation between seminal plasma zinc concentration and serum PRL levels (r = -0.198, p < 0.05). Serum zinc concentration showed a negative correlation with serum T levels (r = -0.207, p < 0.05). Both fructose concentrations and total fructose were significantly low in abnormal volume group compared to normal; 15.30 u.mol/ml (1.52) vs. 44.27 umol/ml (2.44) for fructose concentration and 19.06 umol (2.39) vs. 160.63 umol (16.0) for total fructose, p < 0,0001. Mean fructose concentration was significantly high in oligozoospermic group compared to normal; 45.33 umol/ml (5.02) vs. 35.07 umol/ml (2.39). p < 0.05. Total neutral a -glucosidase activity was significantly low in low volume group compared to normal; 55.37 mU (8.79) vs. 140.93 mU (15.36). p < 0.0001. Seminal plasma total zinc positively correlated with total fructose (r = 0.378, p < 0.001), and NAG (r = 0.247. p < 0.001). In-vitro incorporation of zinc. > 5.0 umol/ml into the processed sperm samples and, > 10 umol/zinc into unprocessed sperm samples, caused an impairment of the progressive motility of sperms. Incorporation of 1.2 umol/ml of zinc into sperm culture medium exerts a significantly beneficial effect on sperm recovery rate. The mean post wash sperm concentration showed an increase in the 1.2 umol/ml of zinc added group compared to the zinc devoid sample; 21.87 million/ml (6.61) vs. 18.34 million/ml (9.73), p < 0.05. The percentage of hyperactwated sperm also increased in 1.2 umol/ml zinc added group compared to zinc devoid group; 46.70 % (3.80) vs. 38.83 % (3.56), p < 0.05. In behavioural studies, supplementation of zinc (5 mg/day) for two weeks led to a prolonged ejaculatory latency; 711.6 Sec. (85.47) vs. 489.50 Sec. (67.66), p < 0.05 and an increase in penile thrusting compared to controls; 52.80 Sec (11.28) vs. 26.50 Sec (6.17), p< 0.05. Similarly the PRL and T levels were significantly increased after the treatment period compared to hormone levels before the treatment; PRL - 7.22 ng/dl (3.68) vs. 2.90 ng/dl (0.34) and T - 8.21 ng/ml (6.09; vs. 2.39 ng/ml (1.79), p < 0.05. In conclusion, this study revealed that zinc is beneficial in male reproduction in different aspects.Item The relationship between asthma and gastro-oesophageal reflux disease(GORD) in a Sri Lankan population(University of Kelaniya, 2009) Amarasiri, W.A.D.L.Gastro-oesophageal Reflux Disease (GORD) predisposes to asthma-like respiratory disease through several mechanisms all of which are thought to be vagally mediated. This study attempted to extend the current understanding of the relationship between GORD and asthma by investigating the prevalence of GORD symptoms, prevalence of upper gastrointestinal motility abnormalities and possible mechanisms of GORD-induced asthma in a group of adults with mild clinically stable asthma in Sri Lanka. The prevalence of GOR symptoms using an interviewer administered GORD questionnaire was 59.4 % in Sri Lankan adult asthmatics. The frequency and severity of GOR symptoms were higher and reflux associated respiratory symptoms were more prevalent in asthmatics when compared to non asthmatics. The severity of asthma showed a strong dose-response effect on the presence of GORD symptoms in asthmatics, though the use of asthma medication did not significantly influence the presence of GORD symptoms. This study reports the development and validation of the first interviewer administered GORD-specific questionnaire in Sri Lanka. This could be used as a case-finding tool in epidemiological studies and be used to assess the response of individuals to treatment. A GORD symptom score using both symptom frequency and severity was found to correlate better with an objective measure of GORD. Using stationary oesophageal manometry and twenty four hour ambulatory pH monitoring, this study demonstrated that asthmatics have abnormal oesophageal motility and increased gastro-oesophageal reflux compared to non-asthmatic healthy volunteers. Asthmatic were seen to have more proximal oesophageal reflux and experience reflux-associated respiratory symptoms, and in most instances, reflux episodes preceded the respiratory symptoms. The presence or severity of GORD symptoms or oesophagitis did not influence the abnormal oesophageal function parameters. Using cutaneous electrogastrography and real-time ultrasonography, this study gives the first report on gastric myoelectrical activity and gastric emptying in asthmatics. Asthmatics have more gastric myoelectrical abnormalities, a significantly lower percentage of gastric emptying and impaired antral mortility in response to both solid and liquid meals compared to non-asthmic healthy volunteers. The antral mortility index and gastric emptying rate of a liquid meal was positively correlated with lower oesophageal sphincter tone in asmatics supporting the theory that delayed gastric emptying and impaired antral mortility induces reflux. Asthmatics with higher GORD symptom scores had lower gastric emptying rates and more abnormal mortility in response to the solid meal. Finally, this study reports the first demonstration of vagal function following intra-oesophageal acid infusion in asthmatics. Asthmatics demonstrated a higher vagal response and a concomitant bronchoconstrictive response to artificially infused oesophageal acid when compared to infusion of normal saline, irrespestive of reflux state.Item Studies on Mycoplasma pneumoniae infections among patients with respiratory illness in Sri Lanka(University of Kelaniya, 2007) Wijesooriya, W. R. P. L. I.Mycoplasmas represent the smallest self-replicating organisms known on the planet. Mycoplasma pneumoniae is the most important human mycoplasma pathogen causing a range of respiratory tract infections including pneumonia. M. pneumoniae causes 50% of primary atypical pneumonia, of primary atypical pneumonia contributing to 15-20% of community acquired pneumonia (CAP).. Apart from pulmonary involvement, it is associated with a range of extra pulmonary manifestations namely; encephalitis, cerebellar syndrome, aseptic meningitis, erythematous / maculopapular rashes, arthralgias, polyarthropathies, myocarditis, pancreatitis, haemolytic anaemia, glomerulonephritis, conjunctivitis etc. As M. pneumoniae does not have a cell wall like bacteria, the conventional treatment (e.g. penicillins) for CAP is not effective. Hence there is a need for prompt and correct diagnosis for effective treatment. As the diagnosis relies on laboratory tests, these may take time. Therefore empirical therapy that is guided by the prevalence data of the particular locality may facilitate treatment. This study was carried out at the North Colombo Teaching Hospital, Ragama and the chest hospital, Welisara during the period from September 2003 to August 2004. The study was to determine the prevalence of M. pneumoniae infection among patients with respiratory tract infections - particularly in three patient groups (pneumonia, acute bronchitis, sore throat) and a control group. Each group consisted of 200 patients. Paired serum samples were obtained from each group for serology antibody tests using M. pneumoniae specific Enzyme-Linked Immunosorbent Assay (ELISA) (isotype specific) and Cold Agglutinin Test (CAT). Respiratory samples from each individual at first sampling were used for detection of M. pneumoniae DNA. Serologically confirmed cases of M. pneumoniae with age and gender were matched with serologically negative group of patients selected for M. pneumoniae DNA PCR. CAT was performed only for patients with pneumonia at acute stage. The prevalence of M. pneumoniae infection by antibody test was 15.5%, 6.6% and 1.2% in patients with pneumonia, acute bronchitis and sore throat respectively. M. pneumoniae DNA was detected in 52% of serology confirmed cases and 15 % of serology negative cases. CAT was positive in 20% of serology positive patients and 20% of serology negative patients. Isotype specific antibody assays are helpful for extended diagnosis. Detection of specific IgM in one sample enabled diagnosis but paired sera was necessary to demonstrate seroconversion when testing for specific IgG. In the study, IgA was shown to be a better indicator of severe infection as this antibody class was observed only in patients with pneumonia. However, specific IgA detection showed low sensitivity. PCR was available to diagnose 15% (4/26) serologically negative patients but it missed serologically positive patients. The combination of antibody serology and PCR detection for M. pneumoniae DNA enabled effective laboratory diagnosis in the clinical setting. The CAT was found to offer no distinct advantage and was no longer recommended even as a bed side screening test due to its poor sensitivity and specificity. In the treatment of pneumonia, the decision on empirical antibiotic regime needs to consider the prevalence rate (15.5%) of most common atypical bacterium M. pneumoniae in Sri Lanka.Item Olfactory impairment in early dementia(University of Kelaniya, 2009) Williams, SIntroduction:The clinical significance of olfactory dysfunction in relation to early dementia has not been adequately studied before despite various studies demonstrating olfactory dysfunction in relation to neurodegenerative disorders especially dementia and more recently, mild cognitive impairment(MCI). Objectives: The objective of this study was to identify olfactory deficits in MCI, Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) and any differential effects. The specific focus being on establishing the utility of olfactory testing in differentiating MCI from normals, MCI from early AD and especially early DLB from early AD. Methods:We recruited patients with early AD(27), early DLB(21), MCI(21) and elderly normals(47) for our study. They were assessed using a 16 item olfactory identification test, an olfactory threshold test using sticks impregnated with differing concentrations of butanol, and an olfactory hedonic tone test with differing concentrations of isoamyl acetate/valeric acid. They also underwent a cognitive battery including the MMSE, HVL T, CLOX testing and a CAMDEX Learning work up when necessary. Medial temporal lobe volume estimation using temporal lobe oriented CT scans and Apolipoprotein E(APOE) status was determined. Results: Patients with MCI, AD and DLB had clinically significant olfactory deficits when compared with normal controls. Patients with mild DLB had the worst olfactory identification ability compared to those with mild AD or MCI, independent of age, cognitive function and sex. Olfactory tests showed useful discriminatory ability between AD and DLB. The decline in left medial temporal lobe width correlated with impaired olfactory function in those with MCI and AD. Smell identification score was a better predictor of AD and MCI from normals, than MTL width. APOE status in conjunction with olfactory dysfunction improved the sensitivity and specificity of a diagnosis of AD from normals. Conclusion: Simple bedside tests of olfactory identification demonstrate significant impairment in MCI, early AD and early DLB. These findings have diagnostic significance particularly in early detection. Smell tests are easier to apply across populations with different educational, language and cultural backgrounds, in comparison to cognitive tests which need extensive validation in different settings. Those with DLB are the most effected and the combination of olfactory dysfunction to existing criteria for diagnosis of DLB has the potential to improve ante-mortem detection of the condition. This has implications for treatment as those with DLB show better response to treatment with choline esterase inhibitors.Item Atopy, allergic diseases and soil transmitted nematode infections in children in Sri Lanka(University of Kelaniya, 2009) Amarasekera, N.D.D.M.Allergic diseases in children are a common paediatric problem affecting approximately one third of children worldwide. Attempts have been made to explain the rising prevalence of allergic diseases, of which the "Hygiene Hypothesis" gained much attention. Though an inverse association between a variety of infection and allergy has been demonstrated, the relationship between helminth infections and allergy remains unclear. A cross-sectional study was carried out in 640 school children selected by stratified random sampling from schools in the Western Province. Data regarding allergic diseases was collected using a validated questionnaire. Children were assessed for intestinal helminth infections by examining their stool samples using the modified Kato-Katz technique. Total IgE and specific IgE for a panel of five allergens (Dermatophagoides pteronyssinus, Blomia tropicalis, cockroach, cat dander and grass pollen) were studied using ImmunoCAP technique in a sub sample of 203. Prior exposure to Toxocara was determined using a commercially available ELISA kit, which detected IgG antibodies. A prevalence of 33.7% for allergic diseases (asthma, rhinitis and eczerna) was observed. Rhinitis was the commonest disease (21.4%). 15.5% of children had one or more intestinal nematode infections. 66.7% of children had antibodies indicative of prior exposure to Toxocara, while 30.6% had evidence of recent infection with Toxocara. Total IgE levels in our study population were intermediate between African and Western populations, but higher than other Asians. The levels were higher in children with intestinal nematode infections and those who were exposed to Toxocara. Total IgE correlated poorly with allergic disease status in the presence of helminth infections. 80.3% of children were found to be sensitized to one or more of the allergens tested; most commonly to dust mites. Children with rhinitis or eczema (but not asthma) were more likely to be sensitized to cat dander. No association was found between sensitization and helminth infections in our study population. Multivariate analysis using logistic regression showed that after adjusting for sex and atopy, children with intestinal nematode infections (especially trichuriasis) had a lower risk of having atopic diseases, especially asthma. Seropositivity for Toxocara spp. was not found to be associated with any atopic disease or atopy.Item Isolation and characterization of influenza viruses circulating among avian, swine and human populations in Sri Lanka(University of Kelaniya, 2007) Perera, K. V. H. K. K.Ecological and phylogenic studies suggest that wild waterfowl are the natural reservoirs of influenza A viruses. All HA and NA subtypes are found in avian species especially wild aquatic birds, whereas viral subtypes of mammalian influenza viruses are limited. Restricted growth of avian influenza viruses in mammalian species is thought to be a barrier to the emergence of new pandemic strains with direct avian to human transmission. In Sri Lanka, although epidemiological and virological studies on outbreaks of influenza on humans have been carried out, there are no reported data on influenza subtypes circulating among human, swine and avian populations during any specified periods. In this study 300 nasopharyngeal aspirates (NPA) obtained from human patients with acute respiratory tract infection, 750 cloacal samples, 750 tracheal samples and 750 blood samples from birds , and 300 tracheal and 300 blood samples from pigs were analyzed to identify the influenza subtypes circulating among these different populations in the country. Of the 300 NPA samples, 138 were screened by the indirect immunofluorescence test followed by the direct immunofluorescence test (DFA) to identify the viral etiological agents responsible for the infection: Influenza A (20/138), para influenza group (2/138), adeno (3/138) and respiratory syncitial virus (3/138) were identified. All 300 NPA samples were inoculated on to MDCK cell cultures and haemagglutination and DFA test were performed on the cultures that showed CPE: 24 Influenza A and 9 Influenza B viruses were isolated and were characterized as Influenza A Panama/2000/99 (H3N2) and Influenza B/Sichuan/379/99-like virus, using reference antisera supplied by the World Health Organization. One virus (Influenza A/swine/Sri lanka/48/04) was isolated from a pig brought to the Government slaughter house in Dematagoda and was sub-typed as H3N2. Genetic studies carried out on this isolate showed that this virus was identical to the H3N2 viruses isolated in humans during the study period. Serological analysis revealed that 61.66 percent of the sampled population also had antibodies to this virus and that none had antibodies to the common subtypes of swine influenza A viruses namely, A/HK/4167/1999 H1N1, A/HK/2422/1998/H3N2 Sydney-like and A/HK/1774/1999 Europian swine-like control viruses. Influenza viruses could not be isolated from the tracheal and cloacal samples collected from poultry when the samples were inoculated into 9-11 day old embryonated eggs. However, the serum collected from this avian population when tested in a HAI assay using H6 (1720) and H9 (Y280) reference antigens, showed evidence of infection with both these subtypes: 12.8 percent (96/750) and 5.2 percent (39/750) of birds had antibodies against A/quail/HK 1721-30/99 (H6N2) and H9 A/duck/ Hong Kong /Y280 (H9N2) subtypes respectively and 3.6 percent had sero-converted to both subtypes of viruses indicating dual infection.Item Molecular diagnosis and transmission of dengue virus in Sri Lanka(University of Kelaniya, 2004) Hapugoda, G. P. G. M. D.Dengue virus is responsible for Dengue Fever (DF), Dengue Haemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). Four circulating dengue serotypes (DEN 1-4) have been identified. Early diagnosis of dengue viral infection helps monitoring the disease, hospital admission when necessary and reduces case fatality. Detection of dengue viruses in mosquitoes is useful to study on transmission of dengue virus. Study on risk factors for dengue is useful to understand spatial and temporal dynamics of transmission the disease. A novel diagnostic assay, Reverse Transcription-Polymerase Chain Reaction-based Liquid Hybridization (RT-PCR-LH) was developed. Amplified products of Non Structural-3 (NS3) gene were hybridized with a mixture of the 4 dengue type specific Deoxyribonucleic Acid (DNA) probes in liquid phase. A high sensitivity of 2 fluorescent focus units of dengue virus/reaction was achieved and the assay was highly specific for dengue virus. This novel assay was first validated for clinical specimens in a preliminary retrospective study using serum specimens known to be dengue positive or negative, according to virus isolation method. Secondly, this assay was validated in a prospective study using serum specimens. As an early (<5 days of fever) laboratory diagnostic method for dengue virus, this assay had 100 percent and 46 percent sensitivity for detection of confirmed and suspected dengue patients respectively. This assay was found to be more sensitive than the other diagnostic techniques: virus isolation, enzyme linked immunosorbant assasy, Haemagglutination inhibition assay and molecular assays based on the same NS3 gene; RT-PCR- mixed phase hybridization, RT-PCR agarose gel electrophoresis (AGE), semi nested PCR-AGE and based on other regions of dengue viruses, for early definitive laboratory diagnosis of primary and secondary dengue infection. Patients with definitive dengue correlated only with few signs and symptoms, indicating that laboratory confirmation is critical to avoid over estimation. Fifty four serum samples were typed; DEN-3 (92 percent) and DEN-2 (7 percent) were found and DEN-3 infected patients in the study population had severe clinical manifestations. This novel technique was also validated to be used for detection of dengue virus in vectors, Aedes aegypti and Ae. albopictus. Wild-caught mosquito samples were collected from 136 dengue case-reported stations during outbreaks and a hot-spot during a period of 31 months. This assay could detect dengue virus in 7 percent of Ae. albopictus specimens. A high density of Ae. albopictus was also associated with the dengue case-reported stations/hot-spots. These results therefore demonstrate that Ae. albopictus acts as an important vector of transmission of dengue in some urban and semi-urban areas. Epidemiological, environmental, entomological and other possible risk factors affecting transmission of dengue were analyzed. Monthly total rainfall, relative humidity and mean temperature having a lag period of 3 months moving average ending with current month can be used to forecast an impending dengue epidemic in a selected hot-spot where a clear seasonal pattern of dengue was evident. Other risk factors affecting transmission are presence of Ae. albopictus, previous dengue patients, untidy garden with mosquito breeding sites and shade of the garden made by vegetation.Item Genetic composition of Plasmodium falciparum in relation to drug resistance and disease transmission in Sri Lanka(University of Kelaniya, 2006) Hapuarachchi, H. C.Malaria has been an important communicable disease in Sri Lanka. Even though P. vivax is the predominant species, there has been an increase in the proportion of chloroquine resistant P. falciparum infections in the country since the early 1990s. According to national data, the highest number of P. falciparum cases has been reported from the Northern Province for several years. This study examined the species distribution, antimalarial resistance, transmission potential and genetic structure of P. falciparum populations among security forces personnel in an operational area of the Mannar District of the Northern Province in 2002 and 2004 to understand their inter-related effects on clinical disease and transmission of malaria in the country. Some of these aspects were compared with those from other areas of the country to determine how they differed in the Northern Province. An attempt was also made for the first time to identify appropriate markers for molecular surveillance of sulfadoxine-pyrimethamine (S-P) resistance of P. falciparum in Sri Lanka. Screening of 1271 patients by light microscopy revealed that P. falciparum was the predominant species in the Northern Province study area. Clinical characteristics of P. falciparum infections (n = 151) suggested that parasite isolates, especially chloroquine resistant ones, in the Northern Province could be more virulent than isolates in other areas. Extended in vivo (n = 76) and in vitro micro test assays (n = 29) for chloroquine showed a treatment failure rate of more than 50 percent among P. falciparum infections in the Northern Province with a 3-fold rise in IC50 values for chloroquine within the two year period. Recrudescent infections caused significantly less severe disease and showed greater potential for transmission than sensitive infections suggesting that antimalarial resistance confers a survival advantage to P. falciparum isolates in the study area. None of the patients (n = 30) who completed in vivo assay for S-P showed evidence of treatment failure. Polymerase Chain Reaction (PCR) based genotyping of P. falciparum populations using size polymorphism in merozoite surface protein-1 (MSP-1), merozoite surface protein-2 (MSP-2) and glutamate rich protein (GLURP) showed a more complex parasite population in the Northern Province. Block 2 of MSP-1, MSP-2 and GLURP were identified as potential markers for genotyping of P. falciparum isolates in Sri Lanka. The proportion of mixed genotype infections and genotype composition of 'pure' P. falciparum infections appears to reflect the transmission intensity in the Northern Province study area. Longitudinal variation in genotype composition of 'pure' infections showed selection of genotypes 2 and 9, which were associated with resistance to chloroquine, providing indirect evidence for the presence of intrahost dynamics in this parasite population. PCR-restriction fragment length polymorphism based mutation analysis of P. falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes that confer resistance to pyrimethamine and sulfadoxine respectively showed that the majority of field isolates in the Northern Province (88 percent) as well as in other areas of the country (75 percent) were double mutants (C59R + S108N) in Pfdhfr. Overall, 18 percent were also mutants in Pfdhps, especially at codon 581 (A581G). Despite the absence of clinical failures with S-P, in vitro yeast expression assay showed a 860-fold higher mean IC50 value for pyrimethamine in the double mutants than in wild type isolates in the Northern Province. In vitro response of those double mutants closely resembled that of yeast cells dependent upon a triple mutant (N51I + C59R + S108N) reference isolate, indicating impending clinical failure to S-P in the country. These results suggest that the mutant codon at residue 51 of Pfdhfr will be the potential marker of imminent S-P clinical failure in Sri Lanka. In conclusion, recrudescent infections appear to drive the phase of tolerance during the evolutionary process of antimalarial resistance as suggested in the "STR model", while primary infections appear to drive the phase of complete resistance in this area. By causing more clinical episodes, chloroquine resistant primary infections probably induce immunity against malaria among individuals, optimizing the evolutionary process of virulence at an intermediate level. A close inter-relationship was evident in P. falciparum genetic structure, antimalarial resistance, clinical disease and disease transmission in the Northern Province. Continued use of chloroquine probably drives the vicious cycle of increasing antimalarial resistance and virulence in the Northern Province. Thus, these results highlight the need to change the current antimalarial therapy in Sri Lanka, particularly in the Northern Province in order to contain the further spread of antimalarial resistance in the country.Item Gastrointestinal mobility in chronic alcoholics(University of Kelaniya, 2001) Ferdinandis, T. G. H. C.The studies presented in this thesis attempt to extend the current understanding of the long-term effects of chronic alcoholism on gastrointestinal motility and the pathogenesis of alcohol related motility disturbances. Chapter 1 discusses the physiology of gastrointestinal motility and effects of alcohol on the gastrointestinal tract with special reference to the problem of alcoholism in Sri Lanka. Chapter 2 compares the results of ambulatory oesophageal manometry and pHmetry in 23 chronic alcoholics and 15 control subjects. The study shows for the first time that chronic alcoholism changes the circadian oesophageal motility pattern. Motility disturbances, such as the failure to increase the percentage of peristaltic waves during the meal period were found to be related to alcoholic autonomic neuropathy. Autonomic neuropathy was also found to be partly responsible for lower oesophageal sphincter hypertension in alcoholics. Changes in contraction amplitude and duration in the distal part of the oesophagus during meal and supine periods were also observed in alcoholics irrespective of the presence of alcoholic neuropathy. Chapter 3 studies the influence of meal consistency on gastric myoelectrical activity using iso-caloric (170 kcal) carbohydrate test meals of different consistency. According to the results obtained from 18 healthy subjects, the solid and the semisolid test meals are capable of increasing the power of the postprandial EGG, while the liquid meal failed to do so. In chapter 4 gastric myoelectrical activity was studied in 18 chronic alcoholics and 10 control subjects using a solid carbohydrate test meal (375kcal). Alcoholics with autonomic neuropathy showed a significantly lower incidence of normal 3cpm wave activity in the postprandial period. Irrespective of the presence of neuropathy, alcoholics failed to increase the power of the EGG following the test meal. In chapter 5, assessed mouth to caecum transit time and colonic transit time as a measure of intestinal motility in 18 alcoholics and 21 control subjects. Lactulose breath test showed a significantly shorter mouth to caecal transit time in alcoholics irrespective of whether they had diarrhoea or not. Rapid intestinal transit seems to have no association with the presence of alcoholic autonomic neuropathy. Assessment of colonic transit using the radiopaque marker ingestion technique failed to show any significant difference in the rate of marker excretion in the alcoholic group compared to the control group. Chronic alcoholism is associated with altered circadian oesophageal motor activity, disturbed postprandial gastric myoelectrical activity and rapid small intestinal transit. The presence of oesophageal motility disturbances and postprandial EGG disturbances together (in alcoholics subjected to both oesophageal manometry and electrogastrography) shows the ability of alcohol in interfering with motor functions of more than one organ at a time. Altered circadian oesophageal motility and postprandial EGG disturbances could partly be attributed to alcoholic autonomic neuropathy.