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Salivary duct carcinoma is a rare and aggressive salivary gland malignancy with a poor prognosis. Due to the paucity of literature, very little is known about this neoplasm. We have described such a case in this case report and highlighted the clinical and histopathological features associated with this disease. A sixty-year old male patient reported in the outpatient department of a regional dental college and hospital with a circular firm growth in the mandibular anterior region and mobility of adjacent mandibular teeth. An array of investigations including radiographic, tomographic, ultrasonographic as well as histopathological were performed. It was diagnosed as invasive salivary duct carcinoma with distant metastases in the shoulder joint, ribs as well as pelvic bones. Currently, no National Comprehensive Cancer Network guidelines for the specific treatment of salivary duct carcinomas exist. National Comprehensive Cancer Network guidelines recommend complete surgical excision of tumors for major salivary gland tumors without nodal involvement (N0) with or without neck dissection for high-grade and T3/T4 salivary gland tumors.
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Florid cemento-osseous dysplasia (COD) represents a rare group of benign fibro-osseous disorders, while osteogenic sarcoma (OS) on the other hand, is a malignant tumour of ominous prognosis. The malignant transformation of a benign fibro-osseous lesion of the jaw is quite uncommon and has few reported cases. The clinico-radiological findings and histopathological analysis of a lesion present in all four quadrants of the jaw of a patient who reported at the outpatient department of a regional dental college is presented here. The lesion underwent sarcomatous transformation over two months and the findings were confirmed by histopathological evaluation. Although florid cemento-osseous dysplasia is a benign lesion of the jaw with a very low propensity for malignant transformation, it should be closely monitored in patients with tumour predisposition syndromes. Further research and molecular studies are required for better understanding of inadvertent changes.
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Leaf blight of the medicinal plants (Piper longum, Tylophora indica and Hibiscus subdariffa) is one of the most significant diseases that severely damage these crops throughout the year in West Bengal .So, management of this disease is essential at now. A few chemical fungicides and trichoderma isolates were tested under in vitro against the disease-associated pathogens in order to identify efficient chemical fungicides and bio agents.It was found that the trichoderma isolates T-2 and T-3 were effective against Colletotrichum gloeosporioides, whereas the isolates T-1 and T-2 were efficient in inhibiting the growth of the test pathogen better against Fusarium sp. and Sclerotium rolfsii.With a higher percentage of inhibition (77.60%), copper oxychloride was the most effective fungicide against Fusarium sp. Conversely, carbendazim and dithane m-45 were more effective against Sclerotium rolfsii and Colletotrichum gloeosporioides, showing 78.33% and 77.93% of inhibition, respectively, and less effective against Fusarium sp at higher concentrations (400 ppm). To determine whether or not these chemical fungicides and trichoderma isolates are effective under in vivo, they will be tested in the field against the corresponding pathogens associated with the disease.
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Introduction: Mucormycosis is an angio-invasive fungal infection that increased significantly during the 2nd wave of the Covid-19 pandemic in India. The rise of cases was attributed to inflammatory changes, poor quality oxygen, immune suppression, and corticosteroid therapy. Case Presentation: This case study reports the history, treatment, and rehabilitation of a case of post-Covid-19 mucormycosis infection. The patient was admitted to the hospital following respiratory distress, at the beginning of the 2nd Covid-19 wave in India. Intravenous antibiotics, steroids, and moist O2 were administered, intensive support was provided and the patient was discharged after 13 days. Following extraction of 17, the patient reported signs of oro-antral communication which was managed by performing antral lavage and buccal advanced flap closure. Histopathological investigation of tissue salvaged during the procedure revealed the presence of fungal hyphae. Management and Prognosis: Following diagnosis, anti-fungal medication was prescribed, and a maxillectomy was performed to remove the affected tissue. On follow-up, the tissue healed with no further complications or symptoms, and rehabilitation was performed using an obturators and are movable complete denture. Histopathological investigations were carried out on the tissue salvaged during maxillectomy which confirmed Mucormycosis infection. Conclusion: The importance of histopathological investigation in the diagnosis of any infectious disease is enumerated in this paper
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Background: Malaria is one of the most severe public health problems worldwide. India contributes a substantial burden of malaria. It can cause several complications. Aims and Objectives: This study was conducted to determine the association of parasitemia of current malaria with age of patients, hemoglobin level, liver function test (LFT), platelet count, previous history of malaria, and relapse/recrudescence of malaria up to 1 year. Materials and Methods: An observational study conducted in hospital settings included thin and thick smear preparation with Leishman’s staining to determine the parasitemia as per the WHO guidelines from the blood samples of 280 malaria parasite dual antigen (MPDA) kit positive patients and their details were taken during study period of 2 years. Hemoglobin, LFT, and platelet count were tested and they were correlated with parasitemia. The previous history of malaria was taken and follow-up was done up to 1 year for relapse/recrudescence and their association with parasitemia in current disease was evaluated. Statistical tool R was used for data analysis. Results: Age group 20–40 years was most commonly affected with maximum mean percentage parasitemia. Higher parasitemia was associated with higher grade of anemia, LFT derangement, and thrombocytopenia. Disease severity was maximum for mixed infection followed by falciparum and vivax malaria. About 9.28% of patients with the previous history of malaria developed lower parasitemia in current infection. Relapse rate in vivax malaria –2.325% and recrudescence rate in falciparum malaria–12.5%. Conclusion: Malaria parasitemia should be reported routinely as it carries prognostic importance.
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Discharge of textile industrial effluent without proper treatment has become a severe hazard for the animal health and environment worldwide. Therefore, this study was designed to isolate azo dye-degrading bacteria from textile wastewater and evaluate their ability to biodegrade reactive dyes into non-toxic products. The potent bacterial strain which was isolated from textile wastewater was identified as Pseudomonas monteilii strain RZT1 on the basis of 16S rDNA sequence. The isolated bacterial strain exhibited good decolorization ability with yeast extract supplementation as cosubstrate in static conditions for Malachite Green dye. The optimal condition for the decolorization of Malachite Green dye by P. monteilii strain RZT1 were at pH 7.0 and 28癈. Decolorization rates of Malachite Green dye by P. monteilii strain RZT1 were varied with initial dye concentration as follow: 84.8%, 75.4%, 63.4% and 45.5% decolorization for 100ppm, 200ppm, 300ppm and 400ppm initial dye concentration respectively. We investigated the effects of dyes used in the textile industry on the seed germination of Five crops - Rice (Oryza sativa), Wheat (Triticum aestivum L.), Khesari (Lathyrus sativus), Mustard (Brassica nigra) and Bitter Melon (Momordica charantia). It was found that textile dye Malachite Green had negative effect on seed germination and seedling growth in test cultures. The harmful effects of dye on seed germination and early seedling growth parameters were augmented with increase of dye concentration. Interestingly, treatment of the Malachite Green dye with isolated bacteria reduced the adverse effects of that dye on seed germination and seedling growth. Thus, it indicated the potentiality of P. monteilii strain RZT1 for bioremediation of textile effluents into a non-toxic form for plants.
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Due to rapid industrialization and market demand of vibrant textile products, the natural textile dyes have been replaced by the synthetic textile dyes. These synthetic dyes are released in environment with textile wastewater resulting in a major environmental pollution, especially in aquatic ecosystem. Hence, aquatic organisms like fish are highly vulnerable to the pollution caused by dyes of textile wastewater. This study was designed to evaluate the deleterious effects of Basic Red-18 (BR-18) dye on behavior, survivability, haematology and histology of Tilapia fish (Tilapia mossambica) and to minimize these deleterious effects of BR-18 dye by bioremediation with the novel bacteria isolated from textile wastewater. The isolated novel bacteria was identified as Mangrovibacter yixingensis strain AKS2 by 16s rRNA sequencing (Accession no. OM189530). The 30% and 70% mortality rates were observed in fish exposed to commercial BR-18 dye at concentrations of 100 and 200 ppm respectively. Interestingly, the mortality rate of fish was decreased significantly to 10% and 20% when fish were exposed to 100 and 200 ppm BR-18 dye respectively after bioremediation with M. yixingensis strain AKS2. Fish exposed to tap water and bioremediated BR-18 dye solution exhibited typical behavioral responses, whereas fish exposed to commercial BR-18 dye solution exhibited anomalous behavior. Fish subjected to commercial BR-18 dye solution displayed decreased RBC, Hb, but increased WBC levels, demonstrating the dye's haemotoxicity. Contrary, no remarkable haematological toxic effect was found when fish were exposed to bioremediated BR-18 dye indicating the non-toxic character of the bioremediated dye metabolites. Similarly, extensive histological abnormalities in the gill, liver, intestinal, stomach, and heart tissues were seen when fish was cultured in commercial BR-18 dye, but the abnormalities were less significant when fish were raised in bioremediated BR-18 dye. Altogether, it can be concluded that BR-18 dye are toxic to fish, but this toxicity can be minimized by bioremediation with M. yixingensis strain AKS2.
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Aim: To develop economically viable integrated fertilizer prescription equation for recommendation of fertilizers in potato on alluvial soils of Eastern India.Methodology: Soil test crop response (STCR) experiments on potato were conducted in alluvial soils of Eastern India during 2016-17 to assess the relationship between yield and availability of plant nutrients for developing fertilizer prescriptions of desired yield targets. The decision on optimum fertilizer doses for varying yield targets were made on the basis of crop nutrient requirement per quintal of potato production, soil efficiency, fertilizer efficiency, and FYM efficiency computed from field experimental data. The optimum fertilizer doses for different yield targets were validated in farmers’ field for economic and environmental benefits as compared to general recommended doses of fertilizers and farmers’ practice. Results: Targeted yield equation for potato for alluvial soil of Eastern India was developed based on soil test values, nutrient requirement and contribution of NPK from soil and fertilizer sources as well as FYM. The prescription based fertilizer application along with FYM increased tuber yield of potato in farmers’ field. Validity of the yield target for 22 and 24 t ha-1 was tested in farmer’s fields and variation in potato yield obtained from targeted yield was 7.6% to 9.8%. Interpretation: Fertilizer prescription equations and ready reckoner developed for potato will be useful in alluvial soils of Eastern India for large scale recommendations and in regions with similar soil and agro-climatic conditions. By following ready reckoner, a farmer can save 61 kg N, 55 kg P2O5 and 44 kg K2O ha-1 over general recommended dose, approximately equal to Rs. 4800/- per hectare.
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Aim: The aim of the present study was to evaluate the retting of jute (Corchorus olitorius L. and C. capsularis L.) using the endospores of microbial consortium of three strains of Bacillus pumilus with extended shelf-life. Methodology: Endospore and vegetative cells of Bacillus pumilus were tested for viability by introducing them into different temperature, pH, UV radiation and antibiotics. Laboratory, as well as field-trials of jute retting was performed with 6 and 18-months-old endospores and vegetative cells of Bacillus pumilus with estimation of enzymatic activities for comparison of their retting efficiency. Results: Endospores of Bacillus pumilus recorded very high colony forming unit (109 to 108ml-1) compared to their vegetative cells (106 to 104ml-1) after 6 to 18 months of their preservation. Endospores also showed higher resistance to temperature, pH, UV irradiation and antibiotic than their vegetative forms. High colony forming unit and higher release of pectinolytic and xylanolytic enzymes during retting of jute by endospores resulted in complete of jute retting in 10 days with good quality jute fibre compared to talc based formulation. Interpretation: It can be concluded from the study that endospores remained highly efficient in rejuvenating higher CFU and quantitatively larger pool of enzymes to accelerate retting of jute after prolonged preservation. Therefore, the endospores of Bacillus pumilus can be used cost effectively in place of their talc based formulation for higher shelf life of the product, faster retting and better fibre quality of jute.
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Management of high blood cholesterol is the key point for the treatment and prevention of Atherosclerotic Cardiovascular Disease (ASCVD). Till 2013, Adult Treatment Panel III (ATP III) report was the guideline for the physician for blood cholesterol management. The main feature of this guideline was to achieve a particular target cholesterol level by lifestyle modification, dietary changes and lipid-lowering drugs. But the recently released American College of Cardiology (ACC) and American Heart Association (AHA) guidelines shifted attention to Statin use at high-, moderate- or low-intensity instead of chasing a cholesterol goal. This article reviews the main features of this new guideline comparing to the previous one, where appropriate.
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The main objective of the study was to find out students liking regarding the various audio visual aids which can improve the lectures in Pharmacology in future in Nepal.This was a cross sectional questionnaire based study was carried out at Manipal College of Medical Sciences, Pokhara, Nepal between January - July 2013. Chi square test were used for analytical purpose. We calculated odds ratios and their 95% confidence intervals (95% CI).P-value < 0.05 was considered to be statistically significant. Questionnaire validation tests showed that the Alpha Cronbach was 0.68. Two eighty two preclinical medical students participated in the study. Two seventy two students completed the questionnaire completely and their responses were evaluated which gives an overall response rate of 96.45%. 52.6% of the students were males and rest were females. Based on the Nationality 41.2% were Indians followed by Nepali 30.1%, Srilankan 25.7% and Maldivian were 2.9%. According to the students the best teaching aids were combination of teaching aids was opted by 61% of the students followed by power point presentation 31.6%, black board 5.9% and dictating notes 1.5%. Most of the students preferred handouts after lectures 56.6% and 43.4% preferred taking notes during lecture classes. Female student preferred taking lecture notes whereas male students preferred taking handouts after the lecture class. It was found that male student has a [OR 4.834, 95% (CI 2.882, 8.109)] more tendency of taking hand outs after the lecture class as compared to taking down notes during lectures. This finding was statistically significant (P<0.05). It is concluded from the study that a combination of different Audio visual aids, viz. blackboard presentation and power point presentation together can improve the lectures and will facilitate the medical student to understand Pharmacology in a better way.
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Congenital Cystic Adenomatoid Malformation (CCAM) is a relatively rare congenital pulmonary cystic disease. By ultrasonography prenatal diagnosis can be made and most baby born without complication. Some babies need surgery at the first year of life for recurrent respiratory tract infection. Here a case of CCAM in a 10 year old boy is reported who presented with recurrent respiratory tract infection and underwent surgical resection successfully.
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Tea [Camellia sinensis L. (O.) Kuntze] is an economically important plantation crop of India but is prone to attack by several fungal pathogens. Copper based fungicides are being used for decades to control fungal diseases in tea which may lead to accumulation of copper in the soil. The biochemical responses to increasing concentrations of copper (50 to 700 µM) were investigated in the leaves of two cultivars of tea commonly grown in the Darjeeling hills. Exposure to excess Cu resulted in increased lipid peroxidation (level of TBARS increased from 3.5 µmol g-1 f.wt. in control to 12 µmol g-1 f.wt. in TS-520 plants exposed to 700 mM of Cu), reduced chlorophyll content (from 83.7 µg g-1 f.wt. in control to 22.5 µg g-1 f.wt. in TS-520 plants exposed to 700 µM of Cu), higher levels of phenolic compounds(total phenol content increased from 4.54 mg g-1 f.wt. in control to 5.79 mg g-1 f.wt. in TS-520 plants exposed to 400 µM of Cu) and an increase in peroxidase enzyme levels. Two new peroxidase isozymes (POD1 and POD2) were detected in plants exposed to Cu. In addition, biochemical responses in two tested cultivars, TS-462 and TS-520 differed significantly. TS-520 was found to be more sensitive to increasing concentrations of Cu. Superoxide dismutase activity increased progressively from 2.55 U mg-1 protein in control to 5.59 U mg-1 protein in TS-462 but declined from 4.75 U mg-1 protein in control to 3.33 U mg-1 protein in TS-520 when exposed to Cu concentrations higher than 400 µM. A sharp increase in the activity of ascorbate peroxidase (from 0.53 units in control to 2.37 units in plants exposed to 400 µM of Cu) was noticed at the 10th day of exposure in the more tolerant cultivar. On the other hand, catalase levels increased only marginally (from 8.4 to 10.1 units in TS 520 and 8.7 to 10.9 units in TS 462) in both the cultivars. From this study, it appears that Cu exposure led to the production of reactive oxygen species in the leaves resulting in significant lipid peroxidation. Tea plants try to mitigate this oxidative damage through accumulation of phenolic compounds and induction of antioxidant enzymes.
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Esterase isozymic variations were documented in the haemolymph of developed multivoltine and bivoltine silkworm breeds during unfavorable seed crop seasons of May – September using α- and β- napthylacetate separately to identify specific and nonspecific esterase having thermotolerant potentiality. Variations existed in the isozyme pattern with three bands (Est-2, 3 and 4) in pure Nistari race and other developed multivoltine and bivoltine breeds. Est-2 and Est-3 were non-specific esterases as they were observed when both α- and β-napthylacetate was used as substrates separately. Est- 4 band was observed only with α-napthylacetate as substrate and was therefore confirmed to be specific α-esterase band in the haemolymph of silkworm, Bombyx mori L. Zymograms showed that the non-specific esterase band (Est-3) with Rf of 0.43 and specific α-esterase band (Est-4) with Rf of 0.32 predominately withstood a temperature of 70 ± 2oC for a duration of 10 min and were confirmed as thermostable esterases in haemolymph of silkworm, Bombyx mori L. This also categorized the presence of thermostable esterases in developed multivoltine and bivoltine breeds of silkworm, even though the qualitative activity was more in the former than the latter. The qualitative presence of thermostable esterases and their activity could be adopted as an indicative biochemical marker in relation to thermotolerance in silkworm.
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Context: Antracycline-Cyclophosphamide (AC) along with Paclitaxel/Docetaxel, either in combination or sequential regimens, is showing superior results than Anthracycline-containing regimens. Aims: This study was designed to determine whether adding Paclitaxel to a standard adjuvant chemotherapy regimen AC for breast cancer patients would prolong the time to recurrence and survival. Settings and Design: Randomized, prospective, open-labeled, single-institutional study. Materials and Methods: Fifty stage II breast cancer patients accruing 25 patients in each arm, treated between July 2007 and January 2010, were included in the study. Initial surgical treatment was Modified Radical Mastectomy. Systemic therapy was to have begun within 4-6 weeks of the patient's surgery. In the control arm, all the patients were treated with six cycles of adjuvant chemotherapy with AC regimen repeated at an interval of 3 weeks. For the study arm, the patients received adjuvant chemotherapy with three cycles of AC regimen followed by three cycles of Paclitaxel, repeated at an interval of 3 weeks. All the patients of both the arms received locoregional external beam radiotherapy (EBRT) after the entire course of chemotherapy. All the hormone receptor-positive patients received Tamoxifen. Statistical Analysis Used: Statistical analysis was performed using the chi-square test and the Kaplan Meier survival analysis with the log-rank (Mantel-Cox) test. Results: Adding Paclitaxel to AC resulted in a statistically significant disease-free survival. The overall survival was also improved significantly. The toxicity profile in both the arms was comparable. Conclusions: In early and node-positive breast cancer, the addition of three cycles of Paclitaxel after completion of three cycles of AC improves the disease-free and overall survival.
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Anthracyclines/administration et posologie , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/chirurgie , Traitement médicamenteux adjuvant/méthodes , Traitement médicamenteux adjuvant/statistiques et données numériques , Protocoles cliniques , Cyclophosphamide/administration et posologie , Association médicamenteuse/administration et posologie , Femelle , Humains , Paclitaxel/administration et posologie , Taxoïdes/administration et posologie , Résultat thérapeutiqueRÉSUMÉ
A unilateral double testicle is a rare anomaly characterized by migration of one testicle towards the opposite inguinal canal. The commonest erratic development is the more or less incomplete descent of the testicle along the normal route of descent, which is known as cryptorchidism. In ectopia of the testicles, as opposed to cryptorchidism, the displaced testicle does not descend along the usual route but as it migrates downwards it moves into an entirely abnormal position. Usually the migrating testicle remains on its own side of the body but may end up in an unusual position e.g. in the superficial tissue of the inguinal region above the external ring, in the area of the base of the penis, in the upper part of the thigh, in the region of perineum or in the pelvic cavity. In this case, the right and left testicles were found to descend together on the right side, whereas the left side of the scrotum was entirely empty. The case was treated with 'Bilateral Transeptal Subdartos Orchidopexy'. The case reported here is evidently one of extreme rarity as there are about 148 reported cases since the first described by Von Lenhossek in1886.
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Background: The relative contribution of insulin secretion and sensitivity in the development of Type 2 diabetes mellitus (T2DM) vary from population to population due to the heterogeneous nature of the disease. The study was undertaken to evaluate insulin secretory capacity and sensitivity in a Bangladeshi Type 2 diabetic population and to explore the association of some of the anthropometric and biochemical factors known to modulate B-cell function and insulin action. Methods: Ninety one T2DM subjects and 32 age-matched controls were studied for their fasting plasma glucose (FPG), lipids, HbA1c (by HPLC), leptin and C-peptide (ELISA). Insulin secretion (HOMA B) and insulin sensitivity (HOMA S) were calculated by homeostasis model assessment (HOMA). Results: Both insulin secretion and sensitivity were significantly reduced in diabetic as compared to control (HOMA B%, geometric mean±SD, 35.65±1.75 vs. 96.29±1.50, p<0.001; HOMA S%, 68.66±1.71 vs. 104.951.63, p<0.001). However, B-cell dysfunction was predominant than insulin resistance in predicting T2DM as the discriminate function coefficient for HOMA B (1.098) was greater than that for HOMA S (0.821). In T2DM, HOMA B had positive correlation with BMI (r=0.368, p<0.001) and HOMA S was inversely correlated to BMI (r=-0.261, p<0.01), WHR (r=-0.258, p<0.01) and plasma TG (r=-0.233, p<0.001). On multiple regression analysis HOMA B and HOMA S were found to be inversely associated to FPG (p<0.001) and leptin (p<0.05) in T2DM. Conclusions: Both insulin secretory dysfunction and insulin resistance are present in Bangladeshi T2DM subjects, but B-cell failure seems to be the predominant abnormality. BMI, plasma glucose, insulin and leptin are the major determinants of insulin secretory capacity and generalized as well as central obesity, plasma glucose, triglycerides, insulin and leptin are among the major determinants of insulin sensitivity in this population.
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Lasiodiplodia theobromae, a common tea (Camellia sinensis) pathogen, usually does not sporulate or sporulates poorly in common media, which makes spore production difficult. In this study the effects of culture media, carbon source, nitrogen source, temperature, pH and light on mycelial growth and sporulation were evaluated. Among several carbon sources tested, glucose and sucrose were found superior for growth. Potassium nitrate supplemented media showed maximum growth amongst the tested inorganic nitrogen sources while peptone produced maximum growth among the tested organic nitrogen sources. Tea root extract supplemented potato dextrose agar medium was found to be the most suitable for mycelial growth and sporulation of L. theobromae. The fungus grow at temperatures ranging from 40 to 36 degrees C, with optimum growth at 28 degrees C and no growth was noted at 40 degrees C. There was no significant effect of different light period on growth of L. theobromae, but light enhanced sporulation. The fungus grow at pH 3.0-8.0 and optimum growth was observed at pH 6.0. Tea root extract supplemented potato dextrose agar medium with pH 6.0 was the most suitable for production of conidia of L. theobromae at 28 degrees C. Hence this media may be recommended for inoculum production for further studies.
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Ascomycota/croissance et développement , Carbone , Milieux de culture , Concentration en ions d'hydrogène , Mycelium/croissance et développement , Azote , Spores fongiques , TempératureRÉSUMÉ
BACKGROUND & OBJECTIVE: Diarrhoeal disease outbreaks are causes of major public health emergencies in India. We carried out investigation of two cholera outbreaks, for identification, antimicrobial susceptibility testing, phage typing and molecular characterization of isolated Vibrio cholerae O1, and to suggest prevention and control measures. METHODS: A total of 22 rectal swabs and 20 stool samples were collected from the two outbreak sites. The V. cholerae isolates were serotyped and antimicrobial susceptibility determined. Pulsed- field gel electrophoresis (PFGE) was performed to identify the clonality of the V. cholerae strains which elucidated better understanding of the epidemiology of the cholera outbreaks. RESULTS: Both the outbreaks were caused by V. cholerae O1 (one was caused by serotype Ogawa and the other by serotype Inaba). Clinically the cases presented with profuse watery diarrhoea and dehydration. All the tested V. cholerae isolates were sensitive to tetracycline, gentamycin and azithromycin but resistance for ampicillin, co-trimoxazole, nalidixic acid, and furazolidone. PFGE pattern of the isolates from the two outbreaks revealed that they were clonal in origin. Stoppage of the source of water contamination and chlorination of drinking water resulted in terminating the two outbreaks. INTERPRETATION & CONCLUSION: The two diarrhoeal outbreaks were caused by V. cholerae O1 (Inaba/Ogawa). Such outbreaks are frequently seen in cholera endemic areas in many parts of the world. Vaccination is an attractive disease (cholera) prevention strategy although long-term measures like improvement of sanitation and personal hygiene, and provision of safe water supply are important, but require time and are expensive.