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Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareRETROSPECTIVE ANALYSIS OF CHOLECYSTECTOMY PERFORMED IN AN INSTITUTION FOR LOWER SOCIOECONOMIC POPULATION IN INDIA
English0105Tanweer KarimEnglish Subhajeet DeyEnglish Rabishankar SinghEnglish Vivek K. KatiyarEnglishBackground: Gallstones are common in Indian population.Laparoscopy requires longer and steeper learning curve and proper patient selection. Patients belonging to lower socioeconomic group usually present late, develop one or the other complications of cholelithisis prior to surgery and expected to have higher conversion rate, per-operative and post-operative complications. Aims: To study safety and efficacy of laparoscopic cholecystectomy in patients of cholelithiasis by comparing with results of open cholecystectomy in terms of use of post-operative analgesia, operative Time, post-operative hospital stay, morbidity and mortality. Material and Method: Patients operated for gallbladder stone betweenJanuary 2013 and August 2015were retrospectively analyzed in terms of demographic profile, clinical presentation, procedureperformed and its findings, operating time, conversion rate, postoperative pain and analgesic requirement, postoperative hospital stay and complication. Results: Cholecystectomy was performed in 630 patients between January 2013 and August 2015. 368 patients were operated laparoscopically and 232 patients by open method. It comprises of almost 25 percent of major operations performed during this period, 75.8% were females and 9 of them were less than 15 years of age. The mean operating time during 2013 for laparoscopic and open Cholecystectomy was 68.37 minutes and 66.20 minutes, decreased to 46.27 minute and 53.33 minute during 2014-15, respectively. Intraoperative cholangiography was not required in any case. Conclusion: Cholelithiasis is relatively common in India even in lower socio-economic group. Dietary habits and obesity do not appear as contributing factor.Laparoscopy has better visibility, access and operating time than open cholecystectomy. Complications rate is negligible even in difficult gallbladders, if proper planning is done with ultrasonography and liver function test 24 hours prior to surgery.
EnglishLaparoscopic cholecystectomy, Open cholecystectomy, Cholelithiasis, Obstructive jaundice, PancreatitisINTRODUCTION
Laparoscopic cholecystectomy is a revolutionary change in the treatment of patients with gallbladder stones. Mouret introduced laparoscopic cholecystectomy in 1987[1]. It has rapidly replaced open cholecystectomy as the standard treatment. Advantages of laparoscopic cholecystectomy include reduced hospitalization, decreased morbidity, short recovery time, and better cosmesis[2].Laparoscopic cholecystectomy though safe and effective, yet can be difficult at times. Various problems faced are difficulty in creating pneumoperitoneum, accessing peritoneal cavity, releasing adhesions, identifying anatomy, anatomical variation and extracting the gall bladder. Laparoscopic cholecystectomy with these problems along with time taken more than normal is considered as difficult.Pre-operative prediction of a difficult laparoscopic cholecystectomy can help the patient as well as the surgeon prepare better for the intra-operative risk and the risk of conversion to open cholecystectomy.
AIMS To study safety and efficacy of laparoscopic cholecystectomy in patients of cholelithiasis by comparing with results of open cholecystectomy in terms of use of post-operative analgesia, operative time, post-operative hospital stay, morbidity, mortality and factors responsible for conversion.
MATERIAL AND METHOD 630 Patients underwent cholecystectomy between January 2013 and August 2015.Since laparoscopic cholecystectomy has been considered as gold standard we offered this option to thepatients except in cases of gallbladder mass, post ERCP and CBD stenting, cardio-respiratory diseases (ASA grade III/ IV) or where patient’s choice was for open cholecystectomy. Patients have been managed by single unit of department of Surgery, ESIC PGIMSR, Basaidarapur, New Delhi, India, an organization which provides social security and healthcare services to lower socio-economic population.Record sheets of 630 patients operated between January 2013 and August2015 were retrospectively collected. Information regarding demographic profile, clinical features, laboratory and radiological investigations, operating procedure and findings, operating time, Conversion rate, postoperative pain and analgesic requirement, postoperative hospital stay and complication were filled in the proforma. Results were statistically analysed and compared with similar studies.
RESULTS 630 patients of cholelithiasis were operated during January 2013 and August 2015. Out of 630 patients,368 were operated laparoscopically and procedure was completed without conversion. 232 patients had undergone open cholecystectomy and 30 patients had been converted to open cholecystectomy after starting laparoscopically(Figure1). These patients were aged between 8years to 87 years with mean of 42 years, 477(75.8%) females and 153(24.2%) males. Nine of them were less than 15 years of age. The mean operation time during 2014-15 for laparoscopic cholecystectomy is 46.27 minute and 53.33 minute for open cholecystectomy. The mean operating time during 2013 for laparoscopic and open cholecystectomy was 68.37 minutes and 66.20 minutes, respectively (Table 1). The number of laparoscopic cholecystectomy performed during 2014-15 was 240 and mean operating time was46.27 minutes [Median-43+43/2=43, Range=85 and Mode=45]. During the same period total number of open cholecystectomy was 160 and mean operating time was53.33 minutes [Median was 45+45/2=45, Range=79 and Mode=45]. The number laparoscopic cholecystectomy during 2013 was 133, Mean operating time was 68.37 minutes [Median=66, Mode=65,66 and Range=65].
During same period the number of open cholecystectomy was 76 and mean operating time was 66.20 minute [Median=65+66/2=65.5, Range=68.42 and Mode=66]. Total number of laparoscopic cholecystectomy converted to open were 21, 6 and 3 during 2013, 2014 and 2015, respectively. Laparoscopic cholecystectomy was converted to open cholecystectomy in 13 grossly thickened gallbladders not amenable to grasp, 6 cases of contracted gallbladder post ERCP, 5 cases with previous upper abdominal surgery and adhesions all around, 3 cases of suspected carcinoma gallbladder and 3 cases of Mirrizi Syndrome(Figure 2a, 2b). It has been observed that duration of post-operative pain and analgesia required were significantly lesser in laparoscopic cholecystectomy group than open cholecystectomy group. The use of Injectable analgesics in cases of laparoscopic cholecystectomy was maximum for 2 days and it was never less than 3 days in cases of open cholecystectomy(Table2).
Bile leak was present in 3 cases of laparoscopic cholecystectomy during 2013 and one case in 2014. Two of them had leak from cystic duct stump due to distal common bile duct stone. One patient had minor leak from injury to right hepatic duct and one had tear at the confluence of cystic duct and common hepatic duct. MRCP (Magnetic resonance cholangiopancreatography) followed by ERCP (Endoscopic retrograde cholangiopancreatography) and stenting was done in all the cases and flat drain was already placed during surgery. They all recovered within a week time and their stent were removed later. Three patients of open cholecystectomy had minor biliary leak without demonstrable extrahepatic biliary injury on MRCP.
Two patients were diagnosed as cases of Dubin Jonson Syndrome, suspected because of abnormal dark color of liver, hyperbilirubinemia, normal liver enzymes and histopathology has not corroborated with other liver pathology. Wound infection was present in 13 cases of open cholecystectomy only. Therefore, rate of complication and conversion has apparently decreased with better planning and experience. Post-operative hospital stay for laparoscopic group was 2.56 days(Range 1-6 days), whereas it was 3.86 days with range of 2-10 days in open group. Common comorbid conditions were diabetes mellitus, hypertension and hypothyroidism. Majority of cholelithiasis patients have grade 1 or II fatty liver on ultrasonography. However, their dietary habits do not show any specific pattern.
DISCUSSION Very few operations have changed the thinking and operating habits of surgeons as quickly as laparoscopic cholecystectomy. This technique of small incision for cholecystectomy has shown good result in terms of reducing pain and morbidity and paved the way for use of minimal access surgery. Laparoscopic cholecystectomy was first performed in Lyon, France in March 1987 by Philippe Mouret, a general surgeon.[1-4]. The extent to which the surgical incision contributes to morbidity and mortality is well established. Sufficient time has elapsed since the first laparoscopic cholecystectomy was performed.
Most surgeons have passed through the learning curve phase of their experience and have now settled into established patterns of activity. There are studies which show thatthe natural history of incidentally discovered gallstone is not only benign but even when they do develop complications; it is usually preceded by at least one episode of biliary pain and longer the stones remain asymptomatic, the less likely it is that complications will occur. In about 30%, patients who have had pain do not have further episodes of pain. Thus, for persons with asymptomatic gallstones, the natural history is so benign that not only treatment but also a regular follow-up is not recomrnended[5-6].
However, our experience with longstanding cases of cholelithiasis isdifferent and more often than not they present with one or the other complication preoperatively and pose difficulty during surgery. Laparoscopic cholecystectomy changed the view of the surgeons and the patients towards asymptomatic gallstones. After the introduction and widespread use of laparoscopic cholecystectomy, a significant change has been observed possibly due to the attitude of surgeons to relax the indication of surgery, including for asymptomatic gallstone, resulting in an increase in cholecystectomies worldwide. Laparoscopic cholecystectomy in young patients with uncomplicated, asymptomatic gallstones is safe with greater patient acceptance, and this approach in early age eliminates the need for problematic surgery at a later date when the patient is older, with associated diseases or with complications [7-10].
The chance of slipping into CBD is high and complications like obstructive jaundice, cholangitis and pancreatitis are likely [11]. Conversion rates in laparoscopic cholecystectomy ranges from 3% to 15% in well trained hands. In our series composite conversion rate is less than 8%during 2013 which has gone down further to less than 4 percent during 2014-15(Table 3). The frequency of bile duct injury is 0.1 % to 0.2% for open cholecystectomy and 0.3% to 0.6% for laparoscopic cholecystectomy. Two most common reasons for conversion are dense upper abdominal adhesions and thickened gall bladder wall that precludes grasping and elevation with grasper.
Common risk factors for conversion are male gender, obesity, cholecystitis (especially after 48 to 72 hours after onset of symptoms) and choledocholithiasis. Most conversions happen after a simple inspection or a minimum dissection, and the decision to convert should be considered as a sign of surgical maturity rather than a failure. Conversion should be opted for in the beginning and at the time of recognition of a difficult dissection rather than after the occurrence of complication. It is vital for the surgeons and patients to appreciate that the decision to go for conversion is not failure but rather implies safe approach and sound surgical judgment. It is therefore mandatory to explain the patients about possibility of conversion to open technique at the time of taking consent for laparoscopic cholecystectomy [12-13].
Postoperative pain is less compared with open traditional cholecystectomy. However, overall pain after laparoscopic cholecystectomy carries a high inter individual variability in intensity and duration. Pain is most intense on the day of surgery and on the following day and subsequently declines to low levels within 3–4 days. Wound infection in open procedure is 3 times the laparoscopic procedures. Jatzko et al in their study observed that complications rate is lower in laparoscopic cholecystectomy group (0.3%) as compared to open cholecystectomy group (5.1 %). Barkun JS et al in a study also observed that number of complications in laparoscopic cholecystectomy were significantly less than number of complication in open cholecystectomy. Laparoscopic surgery could increase the morbidity and mortality of surgery particularly in elderly patients with limited cardiopulmonary reserve.
Laparoscopic surgery has been theoretically associated with compounding cardiac problems because the intra-abdominal pressure coupled with head up position results in pooling of blood in legs, reduced venous return, hypotension and increased tendency to develop venous thrombosis. Pressure effects of Carbon dioxide gas insufflated, may have effect on venous return, the heart rate and rhythm, basal lung expansion, carbon dioxide retention and acidosis[14-15].
CONCLUSION Difficult laparoscopic cholecystectomy is relatively common in India even in lower socio-economic group. All patients should undergo ultrasonography of abdomen and liver function estimation a day prior to surgery in order to assess gallbladder and common bile duct status and plan accordingly. There is a need to stick to maximum time limit in difficult cases to avoid complications due to surgery or prolonged anesthesia. During the study period operation time for laparoscopic cholecystectomy has shown a tendency to become shorter and conversion rate has shown a decreasing trend probably due to better planning and experience.
ACKNOWLEDGEMENT Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors/ editors/ publishers of those articles, journals and books from where the literature for this article has been reviewed and discussed.
Conflict of interest: None
Source of Funding: None
Englishhttp://ijcrr.com/abstract.php?article_id=358http://ijcrr.com/article_html.php?did=3581. Mouret P. From the first laparoscopic cholecystectomy to frontiers of laparoscopic surgery; the future perspective. Dig Surg. 1991;8:124–125
2. Ellis H. John Stough Bobbs: father of gall bladder surgery. British journal of hospital medicine London England 2005. 2009;70(11):650.
3. Traverso LW. Carl Langenbuch and the first cholecystectomy. [Internet]. American journal of surgery. 1976. p. 81–2.
4. Paulino-Netto A. A review of 391 selected open cholecystectomies for comparison with laparoscopic cholecystectomy. American journal of surgery. 1993; 166 (1):71–3.
5. Cheslyn-Curtis S, Russell RC. New trends in gallstone management. The British journal of surgery. 1991;78(2):143–9.
6. Villanova N, Bazzoli F, Taroni F, Frabboni R, Mazzella G, Festi D, et al. Gallstone recurrence after successful oral bile acid treatment. A 12-year follow-up study and evaluation of long-term post dissolution treatment. Gastroenterology. 1989;97(3):726– 31.
7. Escarce JJ, Chen W, Schwartz JS. Falling cholecystectomy thresholds since the introduction of laparoscopic cholecystectomy. JAMA 1996;91(20):2653–4.
8. McSherry CK, Ferstenberg H, Calhoun WF, Lahman E, Virshup M. The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Annals of Surgery. 1985;202(1):59–63.
9. Lam CM, Murray FE, Cuschieri A. Increased cholecystectomy rate after the introduction of laparoscopic cholecystectomy in Scotland. Gut. 1996;38(2):282–4.
10. Jani K, Rajan PS, Sendhilkumar K, Palanivelu C. Twenty years after Erich Muhe: Persisting controversies with the gold standard of laparoscopic cholecystectomy. Journal of Minimal Access Surgery; 2006;2(2):49–58. A
11. Thompson JS, Philben VJ, Hodgson PE. Operative management of incidental cholelithiasis. American journal of surgery. 1984;148(6):821–4.
12. Alponat A, Kum CK, Koh BC, Rajnakova A, Goh PM. Predictive factors for conversion of laparoscopic cholecystectomy. American journal of surgery 2002;21(3):254–8.
13. Domínguez LC, Rivera A, Bermúdez C, Herrera W. Analysis of factors for conversion of laparoscopic to open cholecystectomy: a prospective study of 703 patients with acute cholecystitis. Cirugia Espanola. 2011;89(5):300–6.
14. Barone JE, Lincer RM. Correction: A prospective analysis of 1518 laparoscopic cholecystectomies. The New England Journal of Medicine. 1991. p. 1517–8.
15. Kane RL, Lurie N, Borbas C, Morris N, Flood S, McLaughlin B, et al. The outcomes of elective laparoscopic and open cholecystectomies. Journal of the American College of Surgeons. 1995. p. 222–3.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcarePERCEPTION OF 2ND YEAR MBBS STUDENTS TOWARDS STUDENT- LED SEMINAR AS SMALL GROUP TEACHING METHOD
English0608Supriya PandaEnglish D. Vijaya BharathiEnglish R. Sarath BabuEnglish K. Bhaskar RaoEnglishObjectives: To introduce interactive teaching method like interactive student-led seminars and to know perception of students towards this method of teaching. Methods: The present batch of 4th semester undergraduate students (160 numbers) was divided into 4 batches of 40 students each after taking written consent from them. They were given the topics for the seminar 1 month prior for preparation. Seminar was conducted in four practical hours. Feedback forms were evaluated by 5-Likert’s Scale. Results: Out of 160 students, 139 students participated in the seminar. Out of 139 students participated, 111 students (79.86%) agreed that it stimulated them to think critically at the subject, 130 students (93.53%) agreed that it assisted their learning and 110 students (79.14%) agreed that it encouraged their participation and made them feel like team members. Conclusions: Student-Led Seminar as small group teaching method is more effective in deep understanding of the subject and critical thinking than didactic lectures and helps the students to improve the communication skills.
EnglishSmall group teaching, Student-Led seminar, PerceptionINTRODUCTION
In majority of the medical colleges in India theory classes are being taken by didactic lectures, which is a passive method of teaching. In this method, there is little retention of memory and student attention decreases after 20 minutes. Therefore, there is a need to introduce interactive teaching methods like interactive student-led seminars and small group discussions. In interactive student-led seminars, participants obtain increased understanding of the subject, develop greater ability to assemble and present information, welcome opportunities to think critically, become more articulate and speak better in public with increased confidence and are stimulated for self-learning(1,2).
AIMS AND OBJECTIVES: 1) To conduct student-led seminars for undergraduate students as interactive teaching in the department of Microbiology, MIMS, Vizianagaram. 2) To get the filled feedback form from the students to evaluate this method of teaching.
METHODOLOGY The present batch of 4 th semester undergraduate students (160 numbers) was divided into 4 batches of 40 students each after taking written consent from them. They were given the topics for the seminar 1 month prior for preparation. We have chosen the topic “Immunology “because it is a subject to understand by critical thinking and correlation. The students who presented the seminar were selected randomly. It was conducted during practical hours in batch-wise in the month of July 2015.Four practical hours (one hour per day and two hours per week) were utilized for the same. Feedback forms were given to the student immediately after completion of the seminar and were received from them after filling of the form. Sufficient time was given to fill up the forms. These were evaluated by 5 –Likert’s scale grading.
RESULTS Out of 160 students, 139 students participated in the seminar. The table number-1 shows the result of filled feedback forms received from the students. Out of 139 students participated, 111 students (79.86%) agreed that it stimulated them to think critically at the subject, 130 students (93.53%) agreed that it assisted their learning and 110 students (79.14%) agreed that it encouraged their participation and made them feel like team members. Fifty percent of the students did not respond to the open ended questions. Thirty one students have written there is better understanding of the subject, 22 students who were the presenters, have written there is improvement in communication skills and 9 students requested to conduct the seminars regularly. Improvement suggested by the students:
1) More students to be involved as presenters in the seminars.
2) Topic to be small and specific.
3) To increase the time allotted for each topic.
DISCUSSION In the present study, majority of the students agreed that interactive student-led seminars helped them to think critically with better understanding of the subject. The students, who presented seminar, felt that there is loss of stage fear with improvement in communication skill. K.G. Gomathi et al found that student led seminars encouraged students in self, active and peer-learning. Teamwork and communication skills were also learnt effectively (3). Zuzana de Jong et al. found that small group tutorial lead to greater satisfaction but better learning results were obtained with interactive seminars (4). In our study, majority of the students agreed that it made them feel like a team member. This is a good training for them as teamwork is being increasingly emphasized in healthcare and team training is now considered essential in medical education (5).
CONCLUSIONS: From the results obtained in the present study, it is concluded that:- 1) Seminar as small group teaching method is more effective in deep understanding of the subject and critical thinking than didactic lectures. 2) It helps the students to improve the communication skills.
ACKNOWLEDGEMENT We acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors /publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.
Englishhttp://ijcrr.com/abstract.php?article_id=359http://ijcrr.com/article_html.php?did=3591. Henry Walton (1997) Small group methods in medical teaching. Medical Education 31,pp459-464.
2. Mc Crorie P (2006) Teaching and leading small groups. Association for the study of medical education, Edinburgh.
3. Kadayam Guruswami Gomathi, Ishtiyaq Ahmed Shaafie and Manda Venkatramana1 Student-Led Seminars as a teaching-learning method- effectiveness of a modified format .South East Asian Journal of Medical Education.2014,Vol. 8 no. 1,pp 82.
4. Zuzana. de Jong, Jessica AB van Nies, Sonja WM Peters, Sylvia Vink, Friedo W Dekker and Albert Scherpbier. Interactive seminars or small group tutorials in preclinical medical education: results of a randomized controlled trial. BMC Medical Education. 2010, 10:79
5. Lerner, S., Magrane, D. and Friedman, E. (2009) Teaching Teamwork in Medical Education. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine. 2009,76, 4, pp. 318-329.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareCORRELATION OF DISEASE DURATION, SMOKING PACK YEARS AND FEV1% PREDICTED WITH BAEP PARAMETERS IN PATIENTS OF COPD
English0915Rupali ParlewarEnglish Rubiya ShaikhEnglishCOPD is a progressive disease associated with an amplified chronic inflammatory response to noxious particles or gases in the airways and lungs. It is characterized by airflow limitation that is not fully reversible. Long term exposure to lung irritants that damages the lungs and airways usually is the cause of COPD. Worldwide, the most commonly encountered risk factor for COPD is tobacco smoking. The early detection of auditory impairment can be possible by recording of BAEP in patients of COPD. Study includes 100 individual, all males with the age group of 40-60 yrs. were divided in two groups, study group (n=50) and controls (n=50). Study group includes patients of COPD, as per gold criteria and those had a duration of COPD for more than 5 years with stable course of disease. Controls are age & sex matched normal healthy adults. Spirometry was done in patients to confirm the diagnosis of COPD and the severity of airflow limitation. And BAEP recording was done. Latencies of wave I, II, III, IV, V and Interpeak latencies I-III, III-V, I-V of right ear had a statistically non-significant positive correlation with disease duration. There were increase in right ear latencies of wave I, II, III, IV, V and Interpeak latencies of I-III, III-V, I-V along with increase in smoking pack years indicating a positive correlation with p value EnglishBAEP, Latencies, Interpeak latencies, FEV1 % predicted value, Smoking pack years, Disease duration, HypoxiaINTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable disease, is characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients (1). The term COPD is commonly used to refer the related conditions emphysema and chronic bronchitis (2).The recently published GOLD report (2014) used the term emphysema and chronic bronchitis for diagnosis of COPD, but they are not included in definition. Because chronic bronchitis defined as the presence of cough and sputum production for at least 3 months in each of 2 consecutive years, is not necessarily associated with airflow limitation. Emphysema, defined as destruction of the alveoli, is a pathological term that is sometimes (incorrectly) used clinically and describes only one of several structural abnormalities present in patients with COPD and can also be found in subjects with normal lung function (1). Long term exposure to lung irritants that damages the lungs and airways usually is the cause of COPD. Worldwide, the most commonly encountered risk factor for COPD is tobacco smoking(3,4,5). Studies show that approximately 80-90% of patients with COPD have been smoking and approximately 15% of all smokers will develop COPD (6). Non-smokers may also be at risk for developing COPD as a consequence of passive smoking, indoor and outdoor air pollution or occupational dusts and chemicals(7,8). COPD risk is related to the total burden of inhaled particles a person encounters over their lifetime (9).
1) Tobacco smoke includes cigarette, bidi, pipe, cigar and other types of tobacco smoking.
2) Indoor air pollution from the burning of biomass fuel used for cooking and heating in poorly vented dwellings, a risk factor that particularly affects women in developing countries (10).
3) Occupational dusts and chemicals are risk factors when the exposures to them are sufficiently intense and prolonged (7,11).
4) Outdoor air pollution also contributes to the lungs’ total burden of inhaled particles, although it appears to have a relatively small effect in causing COPD (1).
5) Genetic factors- The genetic risk factor that is best documented is a severe hereditary deficiency of alpha-1 antitrypsin (12).
These indicators are not diagnostic themselves, but the presence of multiple key indicators increases the probability of a diagnosis of COPD. Spirometry is required to make a clinical diagnosis of COPD; the presence of a post-bronchodilator FEV1 /FVC < 0.70confirms the presence of persistent airflow limitation and thus of COPD. Spirometry (meaning measuring of breath) is the most common of the pulmonary function tests measures how much air can breathe out (volume) and how fast can blow air out (flow)(13). COPD is often associated with clinical manifestations that include metabolic abnormalities, weight loss, muscle weakness and wasting, anxiety, depression(14), Osteoporosis, Cardiovascular diseases like Corpulmonale(15), Atherosclerosis, ischemic heart disease and stroke(16). Many of the systemic co-morbidities associated with COPD have been related to systemic inflammation (17). There is rapidly growing body of evidence indicating that the pulmonary disease observed in patients with COPD is also associated with systemic inflammation(18). COPD is associated with systemic inflammation, recognized as a risk factor for its systemic complications. Hypoxemia triggers oxidative stress and inflammation in COPD patients (19).
The existing medical literature suggests that hypoxemia results in peripheral nerve damage by harming the vasonervosum. In the early stages of ischemia, mechanisms to reduce peripheral neuropathy are activated, but these become insufficient over time and obvious neuropathy is inevitable in chronic hypoxemia (20). There are some studies showing that auditory receptors are affected from hypoxia (21,22). The early detection of auditory impairment can be possible by recording of BAEP in patients of COPD. Brainstem auditory evoked potentials (BAEPs) are the potentials recorded from the ear and vertex in response to a brief auditory stimulation to assess the conduction through the auditory pathway up to the midbrain (23). BAEP is a far field recording of the synchronized response of a large number of neurons in auditory pathway. The use of the BAEP has been well documented both from a neurological and audio logical stand point (24).
BAEP is a simple, non-invasive procedure to detect early impairment of acoustic nerve and CNS pathway, even in the absence of specific symptoms. Therefore Correlation of disease duration, smoking pack years and FEV1 % predicted with BAEP parameters done in patients of COPD.
MATERIALS AND METHODS
The present study was conducted in the Department of Physiology and Department of Pulmonary Medicine in Grant Government Medical College and J.J Hospital, Mumbai. Before commencement of study, approval was taken from the Institutional Ethical Committee.
The study design involved 100 individuals which can be divided in two groups. Group I –Diagnosed patients of COPD as per GOLD criteria, after applying inclusion and exclusion criteria were accepted for study (n=50) Group II –Age and sex matched normal healthy adults (n=50). In addition, spirometry was done to confirm the diagnosis of COPD and the severity of airflow limitation was determined by GOLD gradation criteria (post-bronchodilator FEV1 /FVC ratio less than 70%, consistent with airflow limitation that is not fully reversible,GOLD criteria).
The evaluation was done in following stages -
1) A written informed consent was taken from all participants of this study.
2) A detailed history-taking and thorough clinical exami- nation was done.
3) Spirometric test was performed in both groups and diagnosis of COPD was confirmed in cases
4) BAEP recording was done. Among COPD patients, those had a duration of COPD for more than 5 years with stable course of disease, having a regular follow up for 1 year with no hospitalization for COPD related illness in preceding 6 months were included in study group. All COPD patients in study were males and had smoking history. They were having moderate to severe airflow limitation. The subjects who met the criteria were selected for the study. The study and control group were selected as per inclusion and exclusion criteria. Spirometry test was done in study group with the help of MEDGRAPHICS Body Plethysmographmachine.
Inclusion criteria for selection of COPD patient -
1. Males with age group of 40-60 years.
2. On spirometric test, patients having post-Bronchodilator FEV1 % predicted valueless than 80% with FEV1 / FVC ratio Englishhttp://ijcrr.com/abstract.php?article_id=360http://ijcrr.com/article_html.php?did=3601. Global Initiative for Chronic Obstructive Lung Disease - Global Strategy forthe Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2014. P 1-11. available from http.//www.goldcopd.org.
2. DM Mannino. Epidemiology and Evaluation of COPD. Hospital Physician 2001;p 22-31.
3. Edwin K, Siverman, Frank E. Speizer. Risk factors for the development of chronic obstructive pulmonary disease. Medical clinics of North America. 1996; 80 (3): 501-22.
4. Laniado-Laborín R. Smoking and chronic obstructive pulmonary disease (COPD).Parallel epidemics of the 21 century. Int J Environ Res Public Health. 2009Jan;6(1):209-24.
5. Decramer M, Janssens W, Miravitlles M. Chronic obstructive pulmonary disease. Lancet. 2012; 379 (9823):1341-51.
6. Maarten Fischer, Margreet Scharloo, John Weinman, Ad Kaptein. Illness perceptions and treatment beliefs in pulmonary rehabilitation for patients with COPD, Chapter 2 Respiratory rehabilitation. Psychological management of physical disabilities: A practitioner’s guide. London: Brunner Routledge; 2007. pp. 124-48 available from URL: https://openaccess.leidenuniv.nl
7. Devereux G. ABC of chronic obstructive pulmonary disease. Definition, epidemiology and risk factors. BMJ. 2006;332(7550):1142-4.
8. Rennard, Stephen. Clinical management of chronic obstructive pulmonary disease.2013;2ndedition.New York: Informa Healthcare. p 23.
9. Goldman, Lee. Goldman’s Cecil medicine. 2012; 24th ed. Philadelphia: Elsevier/Saunders. p. 537.
10. Kennedy SM, Chambers R, Du W, Dimich-Ward H. Environmental and occupational exposures: do they affect chronic obstructive pulmonary disease differently in women and men? Proc Am Thorac Soc. 2007 Dec;4(8):692-4.
11. Kant S, Gupta B. Role of lifestyle in the development of chronic obstructive pulmonary disease: a review. Lung India. 2008 Apr;25(2):95- 101.
12. Stoller J K, Aboussouan L S. Alpha 1-antitrypsin deficiency. Lancet 2005;365:2225-36.
13. National Heart, Lung and Blood Institute. National Institute of Health. How Is COPD Diagnosed? p 3. Available from http:// www.nhlbi.nih.gov/Health/Health-topics/copd/
14. Hanania NA, Mullerova H, Locantore NW et al. Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. Am J RespirCrit Care Med 2011; 183:604-11.
15. Weitzenblum E, Chaouat A. Corpulmonale. Chron respire Dis. 2009; 6(3):177-85.
16. Curkendall SM, Lanes S, de Luise C stang MR, et al. Chronic obstructive pulmonary disease severity and cardiovascular outcomes. Eur J Epidemiol. 2006; 21: 803-13.
17. Agusti A, Faner R. Systemic inflammation and comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2012; 9(2): 43-6.
18. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111 (12): 1805-12.
19. G.L. Snider. Understanding of inflammation in chronic obstructive pulmonary disease: the process begins. Am J Respir Crit Care Med. 2003; 163: 1045-46.
20. Pfeifer G, Knuze K, Bruch M, et al. Polyneuropathy associated with chronic hypoxemia: Prevalence in patients with chronic obstructive pulmonary disease. J Neurol. 1990; 237: 230-3.
21. Fowler B, Banner J, Pogue J. The slowing of visual processing by hypoxia. Ergonomics 1993; 36: 727-35.
22. Deecke L, Goode RC, Whitehead G et al. Hearing under respiratory stress: latency changes of the human auditory evoked response during hyperventilation, hypoxia, asphyxia and hypercapnia. Aerosp Med 1973; 44: 1106-11.
23. Mishra UK, Kalita J. Brainstem Auditory Evoked Potential. Clinical Neurophysiology. 2nd ed. Chapter 9.Churchill Livingstone, Elsevier. p 329-46.
24. Charles W Cummings. Otolaryngology Head and Neck Surgery. Volume 5, 4th ed. Elsevier Mosby. 2009; 3470-97.
25. Koul PA. Chronic obstructive pulmonary disease: Indian guidelines and the road ahead. Lung India 2013; 30:175-177.
26. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med. 1995; 152 (5 Pt 2):S77-121.
27. Vijay Kumar, O. P. Tondon. Brainstem auditory evoked potentials (BAEPs) in tobacco smokers. Indian J Physiol Pharmacol. 1996; 40(4): 381-4.
28. Hafez M R, Maabady M H, Aboelkheir O I, Elsheikh R M. Chronic obstructive pulmonary disease and its relation to impairment of visual and brainstem auditory evoked potentials. AAMJ. 2009; 7:3.
29. Nesrien Shalabi, Mohamed Abdel El-Salam, Fatma Abbas. Brain-stem auditory evoked responses in COPD patients. Egyptian Journal of Chest Diseases and Tuberculosis. 2012; 61: 313- 21.
30. Gupta PP, Sood S, Atreja A, Agarwal D. Evaluation of brain stem auditory evoked potentials in stable patients with chronic obstructive pulmonary disease. Ann Thorac Med. 2008;3(4):128- 34.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareA RARE CASE OF PERSISTENT MULLERIAN DUCT SYNDROME PRESENTING AS HERNIA UTERO INGUINALIS
English1619N. MurugesanEnglish M. S. ViswanathanEnglish Lakshmanan S.English Pankaj SuranaEnglish R. AnbhazakanEnglishThe aim of presentation of this rare case of persistent mullerian duct syndrome is to outline management of such case when encountered unexpectedly while operating on obstructed inguinal hernia. More so this possibility should be kept in mind while operating on a case of cryptorchidism. PMDS is a rare condition often missed in a casual USG done in emergency this leads to confusion to surgeon while operating. Left behind gonads pose a risk of malignant degeneration if ignored and hence will need further management. Presence of risk of infertility after definitive treatment especially in young patients precludes immediate surgical removal of gonads in such patients. Proper informed consent prior to such procedure is important as is advise on future fertility.
EnglishPersistent mullerian duct syndrome (PMDS), Pseudohermaphroditism, Transverse testicular ectopia (TTE), Cryptorchidism, Hernia utero inguinalisINTRODUCTION Persistent Mullerian duct syndrome (PMDS) is a rare autosomal recessive disorder which could present as male pseudohermaphroditism in which Mullerian duct derivatives are seen in a male patient. This syndrome is characterized by the persistence of Mullerian duct derivatives (i.e. uterus, cervix, fallopian tubes and upper two thirds of vagina) in a phenotypically and karyotypically male patient.The syndrome is caused either by an insufficient amount of Mullerian inhibiting factor (MIF) or due to insensitivity of the target organ to MIF.
CASE REPORT A 30-year-old male presented to out patient department for a right inguinoscrotal swelling, which was present since 1 year and associated with pain and irreducibility for the past 1 week. Detailed history revealed an associated infertility and he has been married since 4 years. He reported normal sexual activity and had well developed secondary sexual characters. No significant family or personal history was noted. Abdominal examination revealed tense, tender, irreducible right inguinoscortal swelling with absent cough impulse. There were with no signs of intestinal obstruction or strangulation. On genital examination, he had normal male genitalia with normal appearing fully developed penis along with left sided non palpable testis and undeveloped scrotum. The testis on right side could not be appreciated due to tenseness of the hernia. Urgent ultrasound to evaluate revealed absent left testis in left inguinal region and right testis in right inguinal hernia with some ill defined mass in the hernial sac not unlike intestine or bowel. Rest of his lab investigations, ECG and CXR were within normal limits. With a clinical diagnosis of right sided irreducible inguinal hernia with absent testis on left side.
He was taken up for emergency surgery under spinal anesthesia for primarily relieving obstructed inguinal hernia. The exploration of opposite absent left testis was deferred to later date after proper imaging studies. Intraoperatively it was noted that the right hernial sac contained an underdeveloped uterus and bilateral fallopian tube with fimbria like structures. There were two gondal structures on either sides of fallopian tubes which appeared ovoid with smooth surface like testis. There was no evidence of strangulation and the tight neck of hernial sac was released and contents reduced. In order to evaluate, explain and to obtain consent from the patient, these abnormal mullerian structures were not removed in that first setting of open surgery. Mesh repair was done in standard way. His post operative recovery was uneventful. Further evaluations were done to confirm the type of abnormality.
a. Karyotyping was done that revealed 46XY genotype male
b. Tumor markers beta HCG and alpha fetoprotein were within normal limits.
c. CECT revealed uterus and fallopian tubes of almost normal size. Lower end of uterus ended in a cord like tissue that could be traced up to prostate. Bilateral hypoplastic testis were noted intraabdominally. No ovarian tissue was found. There were no abnormalities were noted in kidneys, ureters and bladder.
d. Semen analysis was azoospermic
e. Hormonal analysis revealed normal level of testosterone, oestrogen and progesterone for male
Patient and his wife were appraised and counselled about his condition. The reason for their infertility was explained. The need for removal of the abnormal uterus fallopian tubes and intra abdominal hypoplastic testes was explained. Appropriate consents were obtained for laparoscopic approach after explaining the risks and complications. Three months later under general anaesthesia the persistent mullerian structures uterus, fallopian tubes, vaginal tube up to its entry into prostate and both testis were removed laparoscopically by standard technique as used for laparoscopic hysterectomy with bilateral salpingooophorectomy. Intraoperatively the cervix portion continued as a thick cord of like structure going deep in rectovescical plane. The dissection was taken deep and it was divided close to level of prostate. Post operative course was uneventful. Histopathology of the specimen revealed normal endometrial, myometrial and cervix and fallopian tube histology with normal seminiferous tubules lined by sertoli cells and foci of leydig cells. No epididymal structures found. And there was no evidence of spermatogenesis. Patient was regularly followed and is presently on testosterone replacement therapy. He was advised ART with donor sperm or adoption for infertility.
DISCUSSION Müllerian (paramesonephric) ducts and wolffian (mesonephric) ducts are the anlagen of the female and male reproductive tracts, respectively. In the XY fetus, the testis differentiates by the end of the seventh gestational week. Sertoli cells begin to secrete AMH, which is responsible for the regression of the Müllerian ducts. The AMH binds to a specific Type II serine-threonine kinase transmembrane receptor (AMHR-II). Human AMH gene localized near the tip of Chromosome 19, AMHR2 gene is located on 12q13. The type of persistent Mullerian duct syndrome caused by mutation in the AMH gene will be referred to as Type I, that which forms due to mutation in the AMH receptor (AMHR) will be designated as Type II.[1] In 45%, a mutation of the anti-mullerian hormone (AMH) gene was detected; in 39% mutation of the Type II receptor of AMH was detected; in 16% the cause is unknown.
Transverse testicular ectopia (TTE) or crossed testicular ectopia is a rare form of testicular ectopia. It was first reported by Von Lenhossek in 1886 [2]. More than 100 cases have been reported in the literature [3]. Several theories have been reported to explain the genesis of TTE. Berg [4] proposed the possibility of the development of both testes from the same genital ridge. Kimura [5] concluded that if both vasa deferentia arose from one side, there had been unilateral origin but if there was bilateral origin, one testis had crossed over. Gupta and Das [6] postulated that adherence and fusion of the developing Wolffian ducts took place early, and that descent of one testis caused the second one to follow. An inguinal hernia is invariably present on the side to which the ectopic testis has migrated.
On the basis of the presence of various associated anomalies, TTE has been classified into 3 types: Type 1, accompanied only by hernia (40% to 50%); type 2, accompanied by persistent or rudimentary Mullerian duct structures (30%); and type 3, associated with disorders other than persistent Mullerian remnants (inguinal hernia, hypospadias, pseudohermaphroditism, and scrotal abnormalities) (20%). According to that classification, our case was type 1/2 TTE. TTE associated with fused vas deferens is extremely rare. This condition may hinder the testis from being placed into the scrotum during orchidopexy [7].
The clinical presentation generally includes an inguinal hernia on one side and a contralateral or sometimes a bilateral cryptorchidism [8], [9]. Usually, the correct diagnosis is not made before surgical exploration, like our case, and it is revealed during herniotomy [9]. The diagnosis of TTE can be made preoperatively by using ultrasonography [10] by an experienced sonologist. Patients with TTE are at increased risk of malignant transformation. In fact, the overall incidence of malignant transformation of gonads is 18% [11]. There have been reports of embryonal carcinoma [12], seminoma, yolk sac tumor [13], and tera- toma [11]. Walsh et al. [14] in their study concluded that testicular cancer was nearly 6 times more likely to develop in cryptorchid cases whose operations were delayed until after age 10 to 11 years. Wood et al. [15] in their study showed that risk of malignancy in undescended testicles decreased if their orchidopexy performed before ages 10 to 12 years.
Orchidectomy of ectopic testis should be done, because orchidopexy offers only limited protection against future malignancy if performed after two years of age.[16] Manassero et al reported development of mixed germ cell tumor 18 years after bilateral orchidopexy.[17] Most are known to be infertile but it is preferable to remove ectopic testis, as it is prone for malignancy. If this is necessary on both sides, there is the additional problem of lifelong testosterone substitution which requires efficient patient monitoring and good patient compliance. In cases where this cannot be achieved, compromises, such as temporarily delayed orchidectomy, may be considered.[18] Testis, vas and epididymis are closely adherent running along the uterus and fallopian tubes. This gives rise to difficulty in separating the gonads and the vas without damage. Different surgical methods have been described for safe surgery.
There have been at least three documented reports of adenocarcinoma in the mullerian duct remnants. So, contrary to previous suggestions, now it is recommended to remove the persistent mullerian derivatives. The patient or his family should be completely informed of the diagnosis, the surgical options and the need for long-term follow-up. Finally, genetic counseling must be offered to the patient or his parents because of the possible chromosomal origin of the syndrome.
CONCLUSION This is a rare presentation of persistent mullarian duct syndrome reported few and far in literature. The surgeon operating on inguinal hernia in a cryptorchid patient, need to be aware of management of this condition, when encountered in an emergency situation. The future fertility of the patient need to be kept in mind and counselling before performing the definitive surgery is essential to prevent future litigation. Specimen harvest of sperms and storage for future use could be planned inappropriate setup if the development of testis seems adequate. Laparoscopic approach is ideal and minimally invasive way for definitive removal of remnant mullerian structures.
Englishhttp://ijcrr.com/abstract.php?article_id=361http://ijcrr.com/article_html.php?did=3611. Imbeaud S, Faure E, Lamarre I, Mattei MG, Clemente N, Tizard R, et al. Insensitivity to anti-mullerian hormone due to a mutation in the human anti-Mullerian hormone receptor. Nat Genet. 1995;11:382–8. [PubMed: 7493017]
2. Von Lenhossek MN. Ectopia testis transversa. Anat Anz.1886;1:376-81.
3. Fourcroy JL, Belman AB. Transverse testicular ectopia with persistent Müllerian duct. Urology. 1982; 19(5):536-8. DOI: 10.1016/0090-4295(82)90614-8
4. Berg AA. Transverse ectopy of the testis. Ann Surg. 1904;40:223
5. Kimura T. Transverse ectopy of the testis with masculine uterus. Ann Surg. 1918;68(4):420-5. DOI: 10.1097/00000658- 191810000-00009
6. Gupta RL, Das P. Ectopia testis transversa. J Indian Med Assoc. 1960;16:35:547-9.
7. Chacko JK, Furness PD 3rd, Mingin GC. Presentation of fused vas deferens. Urology. 2006; 67(5):1085.e17-8. DOI:10.1016/j. urology.2005.11.056
8. Feizzadeh Kerigh B, Mohamadzadeh Rezaei M. Crossed testicular ectopia: a case report. Urol J. 2005;2(4):222-3. Available from: http://www.urologyjournal.org/index.php/uj/article/ view/229/226
9. Acikalin MF, Pasaoglu O, Tokar B, Ilgici D, Ilhan H. Persistent Mullerian duct syndrome with transverse testicular ectopia: A case report with literature review. Turk J Med Sci. 2004;34:333- 6.
10. Nam YS, Baik HK, Kim SJ, Lee HK, Park HK. Transverse testicular ectopia found by preoperative ultrasonography. J Korean Med Sci. 1998; 13(3):328-30.
11. Berkmen F. Persistent müllerian duct syndrome with or without transverse testicular ectopia and testis tumours. Br J Urol. 1997; 79(1):122-6.
12. Melman A, Leiter E, Perez JM, Driscoll D, Palmer C. The influence of neonatal orchiopexy upon the testis in persistent Müllerian duct syndrome. J Urol. 1981;125(6):856-8.
13. Eastham JA, McEvoy K, Sullivan R, Chandrasoma P. A case of simultaneous bilateral nonseminomatous testicular tumors in persistent müllerian duct syndrome. J Urol. 1992;148(2 Pt1):407-8.
14. Walsh TJ, Dall’Era MA, Croughan MS, Carroll PR, Turek PJ. Prepubertal orchiopexy for cryptorchidism may be associated with lower risk of testicular cancer. J Urol. 2007; 178(4 Pt1):1440-6. DOI: 10.1016/j.juro.2007.05.166
15. Wood HM, Elder JS. Cryptorchidism and testicular cancer: separating fact from fiction. J Urol. 2009; 181(2):452-61. DOI:10.1016/j.juro.2008.10.074
16. Berkmen F. Persistent mullerian duct syndrome with or without transverse testicular ectopia and testis tumors. Br J Urol. 1997;79:122–6. [PubMed: 9043511]
17. Manassero F, Cuttano MG, Morelli G, Salinitri G, Spurio M, Selli C. Mixed germ cell tumor after bilateral orchidopexy in persistent mullerian duct syndrome with transverse testicular ectopia. Urol Int. 2004;73:81–3. [PubMed: 15263798]
18. Buchholz NP, Biyabani R, Herzig MJ, Ali A, Nazir Z, Sulaiman MN, et al. Persistent mullerian duct syndrome. Eur Urol. 1998;34:230–2. [PubMed: 9732199]
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareIMPACT OF IMMUNOSUPPRESSIVE DRUGS ON SUDANESE RENAL TRANSPLANT RECIPIENTS INFECTED WITH INTESTINAL PARASITES
English2024Lienda Bashier EltayebEnglish Hisham Ali WaggiallahEnglishObjectives:Enteric parasites are important agents of disease throughout the world. And they increasingly have significant role in transplant candidates. Intestinal parasites that are asymptomatic before transplantation may become clinically significant under immunosuppressive treatment. In the other hand some immunosuppressive regimens has anti-parasitic effects that may result, in lower rates of parasitic infections. Methods: Stool samples were collected from renal transplant recipients attending Sudanese Kidney Association hospital and from a control group from January 2012 to April 2012. For the detection of parasites, fresh stool samples were separated into two samples; one was preserved in SAF fixative. From this sample smears were made for permanent stains. The second sample was examined by wet preparation. Modified trichrome staining method was used for permanent smears for microsporidia. Result: All (200) renal transplant recipients were on immunosuppressant drugs; (76.5%) of the study patients were on tacrolimus (prograf) therapy and only (23.5 %) were on cyclosporine A (CsA) therapy. Of the total patients on tacrolimus there (22.5%) were diagnosed with intestinal parasites and only (1.5%) of them were on Cyclosporine therapy. There was statistically significance between immunosuppressant agents and infection with intestinal parasites positivity in group I (P value= 0.019). All details are summarized in (Table 2). Multiple parasitic infections were observed in a total of 5/200 (2.5%) renal transplant recipients and 1/100(1%) controls (p < 0.05). G lamblia,and B. hominiswas frequently seen species as multiple infections in renal transplant recipients. Conclusion: Intestinal parasitic infections should not ignore in renal transplant recipients, So Cyclosporine therapy should be recommended as first line immunosuppressant drugs as well as prophylactic against wide range of parasitic diseases.
EnglishImmunosuppressive drugs, Transplants, Intestinal parasitesINTRODUCTION
Organ transplant recipients can experience serious diseases from infections due to emerging and reemerging parasitic infections. So they are at risk for infections-particularly opportunistic parasites, and occult intestinal infection can remain quiescent for many years, becoming apparent after initiation of immunosuppression because of the continuous administration of immuno-suppressive drugs 1, 2. The impact of intestinal parasitic infection in renal transplant recipients requires careful consideration in the developing world. However, there have been very few studies addressing this issue in Sudan. On the other hand parasitic infections are easily forgotten by clinicians, and they are often regarded as mild, unimportant. However, parasites continue to be a significant health problem and the commonest causes of morbidity and mortality in many parts of the world especially in the developing countries. With increasing ease of international travel and increasing number of immunocompromised hosts, one might expect to see exotic or unusual parasitic infections anywhere in the world.
For instance, several contributing factors affect the prevalence of intestinal parasites in a geographic location, like socioeconomic status, climatic changes, and poor standards of public and personal hygiene 3 . Immunocompromised hosts, including patients withAIDS, solid organ transplantation, and patients on immunosuppressivetherapy, are at higher risk for opportunistic parasiticin fections.Renal transplant recipients (RTRs) are proneto parasitic infections due to immunosuppressive therapy.Giardiasis comprises 0.05), figure 1.
Majority of patients infective with intestinal parasites were in were in age group (21- 40) figure 2. All (200) renal transplant recipients were on immunosuppressant drugs; (76.5%) of the study patients were on tacrolimus (prograf) therapy and only (23.5 %) were on cyclosporine A (CsA) therapy. Of the total patients on tacrolimus there (22.5%) were diagnosed with intestinal parasites and only (1.5%) of them were on Cyclosporine therapy. There was statistically significance between immunosuppressant agents and infection with intestinal parasites positivity in group I (P value= 0.019).9 All details are summarized in (Table 1).
Table 2 shows the magnitude of single and multiple parasitic (poly parasitism) infections in renal transplant recipients and in controls. Multiple parasitic infections were observed in a total of 5/200 (2.5%) renal transplant recipients and 1/100(1%) controls (p < 0.05). The species of parasites was frequently seen as multiple infections in renal transplant recipients were G. lamblia, H. nana and B. hominis. Table 3 summarizes the frequency of enteric parasites among different types of patients receiving Tacrolimus and Cyclosporine A, were the majority of parasites (16%) in patients receiving tacrolimus.
DISCUSSION This study has evaluated the frequency of opportunistic and common intestinal parasitic infections among renal transplant recipients receiving immunosuppressant drugs (Tacrolimus and CsA). There was an association between frequency of parasitic infections and age group, enteric parasites were common in themiddle age group (21- 40) years old, and this may be this age group were more exposed to factors which enhance parasitic infections so continuous health supervision, annual medical examination and prompt treatment of infected renal transplant recipients minimize the infection rates.
In our study, G. lamblia was the first most prevalent parasite detected in cases and control group (8.5% vs. 10%), without significant difference and followed byB. hominis(4% vs. 1%) and H. nana (2% vs.1%). This is concurrent with that reported by M Nateghiet.al (10) who found that G. lamblia is the second most prevalent parasite (10/706).In other study carried out on renal transplant recipients in Brazil, G. lamblia was the third most prevalent parasite (3/16) and S. stercoralis was the common parasite (11/16). The reason is that CsA acts as an immunomodulator enhancing trypanosomes and Giardia multiplication, and exacerbating the infection. This is more or less could explain the higher incidence of giardiasis infection among the population. There are few reports in the literature regarding giardiasis in immunocompromised hosts 13.
With regard to helminthes, Strongyloidesstercoralis, there are considerable reports of cases of S. stercoralis hyperinfection as a consequence of immunosuppressive treatment following kidney transplantation. However, culture of 200 stool specimens from renal patients yielded lack of infection with S. stercoralislarva. The same result obtained by M Nateghi Rostami et.al14.This might be under the influence of parasiticidal action of CsA. Reportedly CsA has reduced the incidence of strongyloidiasis in renal transplant recipients. Although in the analysis of Valvar et al. the most prevalent infection was reported to be S. stercoralis, but none of infected patients received CsA in their immunosuppressive drug protocol 8 .
The low use of cyclosporine A (23.5%) by study participants is likely to affect the overall frequency of intestinal parasites. It is a fact that, the use of Cyclosporine A (CsA) has become a cornerstone in prophylactic immunosuppression among renal transplant recipients. Cyclosporine A with powerful properties of immunosuppression, acts on parasitic infections in various ways 8 . In laboratory models, CsA reduces survival and growth in a wide range of protozoa and helminthes. CsA is apparently antiparasitic against malaria, Schistosoma, adult tapeworms and filarial nematodes. By contrast, it acts as an immunomodulator against trypanosomes and Giardia, by exacerbating the infection. This more or less could explain the higher incidence of Giardiasis among the population reconvening cyclosporine A. There are few reports in the literature regarding giardiasis in immune-compromised hosts 15. In the other hand patients use tacrolimus were more infected with enteric parasites comparing with transplant patients using CsA (16% versus 8%) respectively.
It was evident that multiple parasitic infections were more common in renal transplant recipients (2.5%) than in controls (1%), this is in agreement with Mehdi Azamiet.al16that found (8% vs. 2.2%) in renal transplant recipients and control respectively. In our study, C. parvumoccurred in co-infection with other intestinal protozoan parasites, such as B. hominis, G. lamblia and H. nana. Hence this strongly indicates the facility of worsen immune system in establishment of multiple parasites in immunocompromised patients. Also detection of such common intestinal parasites in both patients and controls could be a reflection of the poor environmental sanitation and personal hygienic practices, which emphasize the need for intervention measures at the community level to reduce the risk factors of acquiring intestinal parasites. So it is very important to target these common infections while treating renal transplant recipients for opportunistic infections in developing countries like Sudan 17.
CONCLUSION Intestinal parasitic infections should not ignore in renal transplant recipients, and giardiasis should be suspected in RTRs with malabsorption syndrome in a developing country like Sudan. So Cyclosporine therapy should berecommended as first line immunosuppressant drugs as well as prophylactic against wide range of parasitic diseases.
ACKNOWLEDGEMENT Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.
Conflict of interests: Authors have no conflict of interest in this research paper .
Englishhttp://ijcrr.com/abstract.php?article_id=362http://ijcrr.com/article_html.php?did=3621. Fantry L. Gastrointestinal infections in the immunocompromised host. Current Opinion in Gastroenterology 2002; 18(1):34-9.
2. Barsoum RS. Parasitic infections in organ transplantation. Exp Clin Transplant 2004; 2 (2):258-67.
3. Syafinaz AN, Hamat RA, Malina O, Siti NM, Niazlin MT, Jamal F Hymenolepis nana in a renal transplant recipient: to treat or not to treat? Med J Malaysia 2011 Aug; 66(3):259-60.
4. Kiran Kumar Mukku, Sreebhushan Raju And Ramesh Yelanati, Refractory Giardiasis In Renal Transplantation: A Case Report Nephrology 20 (2015) 44–48.
5. C. N. Kottona R. Lattesb and the AST Infectious Diseases Community of PracticeParasitic Infections in Solid Organ Transplant Recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S234–S251Wiley Periodicals Inc.
6. Barsoum RS. Parasitic infections in organ transplantation. Exp Clin Transplant 2004; 2: 258–267.
7. Udgiri N, Minz M, Kashyap R et al. Intestinal cryptosporidiosis in living related renal transplant recipients. Transplant Proc 2004; 36: 2128–2129
8. Jay A. Fishman, Infection in Solid-Organ Transplant Recipients. N Engl J Med 2007; 357:2601-14
9. Eltayeb LB, BirarSl, Waggiallah HA. Prevalence of Intestinal Parasites among Renal Transplant Recipients in Khartoum State. IJHSR. 2015; 5(11): 90-95.
10. Linda BashierEltayeb, Sara LaviniaBrair, Awad Ahmed Nasr. Frequency of intestinal parasites with emphasis on opportunistic parasites among renal transplant recipients with and without diarrhea in Sudan 2012. Sudanese Journal of Public Health. 2013; 8 (4): 135-140.
11. Cheesbrough M. District Medical laboratory manual of tropical countries part 1publishied by tropical health technology and butterworth- heinemannlt second edition 1987; 200-214.
12. Patil K, De A, Mathur M. Comparison of Weber Green and Ryan Blue modified trichrome staining for the diagnosis of microsporidial spores from stool samples of HIV-positive patients with diarrhoea. Indian J Med Microbiol. 2008; 26(4):407
13. Chappell LH, Wastling JM. Cyclosporin A: antiparasite drug, modulator of the hostparasite relationship and immunosuppressant. Parasitology 1992; 105 Suppl: S25-40.
14. M Nateghi Rostami, H Keshavarz, E Eskandari, EB Kia, M Rezaeian Intestinal. Parasitic Infections in Renal Transplant Recipients. Iranian J Parasitol 2007; 2(3)16-23209.
15. Valar C, Keitel E, Dal Pra RL, Gnatta D, Santos AF. Parasitic infection in renal transplant recipients. Transplant Proc 2007; 39 (2): 460-2.
16. Mehdi A, MehranSh, Sayed H, Mehdi T. Intestinal parasitic infections in renal transplant recipients. Braz J Infect Dis 2010; 14(1):15-18.
17. Fantry L. Gastrointestinal infections in the immunocompromised host. Current Opinion in Gastroenterology 2002; 18(1):34-9.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareA STUDY OF THE CLINICAL PROFILE OF MALARIA AND ITS COMPLICATIONS
English2530Varsha Shirish DabadghaoEnglish Veer Bahadur SinghEnglish Dayal SharmaEnglish Babu Lal MeenaEnglishObjectives: Malaria is one of the most widespread infection in the tropics, and also one of the most dangerous. There are four main types of malaria of which Plasmodium vivax and falciparum are common in India. There is a huge burden of disease and malaria is responsible for increased mortality and morbidity. This study was undertaken to evaluate clinical profile of P. vivax, falciparum and mixed malaria and to assess the complications of malaria as a whole and of each type. Methods: This was a cross sectional and observational study which was conducted on a hundred patients above age 14 years diagnosed with malaria. Diagnosis of malaria was made by gold standard method of peripheral blood smear examination and rapid tests. For categorical data, chi- square test was used. P < 0.05 was considered as a statistical significance at 95% confidence intervals. Results: In this study, there were 90% survivors and 10% of patients succumbed. Out of 90 survivors, 43 patients (47.7%) had some form of complicated malaria, whereas all patients who succumbed (10) had complicated malaria. The main complications were severe thrombocytopenia in 78% , significant jaundice (bilirubin> 3mg/dl) in 32% , hypotension with a systolic blood pressure (BP) of less than 70mmHg in 23% , renal impairment in 48% , cerebral malaria in 13%, acute respiratory distress syndrome (ARDS) IN 11%, severe anemia (hemoglobin < 5g/dl) in 10% and metabolic acidosis (bicarbonate < 15mmol/dl) in 5%. Conclusions: The complications seen in this study were mainly severe thrombocytopenia, hypotension, jaundice, renal impairment, cerebral malaria, ARDS, severe anemia and metabolic acidosis; severe thrombocytopenia and jaundice being the commonest, and. P. vivax accounted for more patients with hypotension and severe anemia than the other types of malaria.
EnglishP. Vivax, P. Falciparum, Malaria, ComplicationsINTRODUCTION
Malaria is a disease widespread in the tropics, including India. Plasmodium vivax (P. vivax) is the most common prevalent species and Plasmodium falciparum(P. falciparum) the most virulent one worldwide.[1] Malaria is spread primarily by the bite of the female Anopheles mosquito . Malaria ranks third among major infectious diseases in causing deaths after pneumococcal acute respiratory infections and tuberculosis and is a major cause of mortality and morbidity in India.[2] In the case of mosquito-borne transmission, sporozoites, the infective stage injected along with saliva into subcutaneous capillaries, enter hepatocytes. Inside the hepatocytes, each sporozoite begins a phase of asexual reproduction which results in the formation of a schizont containing thousands of merozoites.
The rupture of mature schizonts generates the liberation of merozoites into the bloodstream. The hepatic schizogony lasts approximately 5.5 days in P. falciparum. In case of P.vivax infections, a percentage of parasites may remain dormant in hepatocytes as hypnozoites for several months up to 5 years. The hepatic schizogony is asymptomatic, as only a few number of liver cells is infected. Merozoites reach and invade red cells rapidly to start a process of asexual multiplication (erythrocytic schizogony).Cytokines lead to the myriad manifestations.[3] Severe malaria as described by WHO , is manifested as clinically, impaired consciousness or unrousable coma, prostration, i.e. generalized weakness so that the patient is unable walk or sit up without assistance, failure to feed, multiple convulsions (more than two episodes in 24 h), deep breathing, respiratory distress (acidotic breathing), circulatory collapse or shock, with systolic blood pressure < 70 mmHg in adults, clinical jaundice plus evidence of other vital organ dysfunction, haemoglobinuria, abnormal spontaneous bleeding and pulmonary oedema (radiological).[4] Laboratory findings include hypoglycaemia (blood glucose < 40 mg/dl), metabolic acidosis (plasma bicarbonate < 15 mmol/l), severe normocytic anaemia (Hb< 5 g/dl, packed cell volume < 15%), haemoglobinuria, jaundice (serum bilirubin >3mg/dl) hyperparasitaemia (> 2% or 100,000/μl in low intensity transmission areas or > 5% or 250,000/μl in areas of high stable malaria transmission intensity), hyperlactataemia (lactate > 5 mmol/l) and renal impairment (serum creatinine > 3mg/dl)[4] Recent reports of malaria cases in India showed that 8.8% of the total malaria cases and 4.1% of the total falciparum cases were reported from Western India, hence due to the widespread prevalence of malaria in this region, this study was planned here.[5] Recently, it was shown that P. vivax was responsible for many of the complications traditionally associated with
P. falciparum and mixed malarias. Hence physicians need to know that this type of malaria may not be necessarily benign.[6] Also, literature on mixed malarias is scanty.[7] The aim of this study was to assess the prevalence of different types of malaria and complications as a whole and of each type. This would help primary care physicians to understand the importance of detecting complications early and institute treatment according to the type and presence of complications. Irrational use of anti malarials would therefore be curbed and each complication dealt with accordingly.
METHODS This cross sectional, prospective and observational study was conducted in a tertiary care centre in western India over a period of two years. Institutional ethical clearance was obtained from the college ethical committee and individual consent taken from each patient. For this study, a hundred patients with age more than 14 years, who were admitted to intensive care units and general medicine wards with a diagnosis of malaria done by a standard peripheral blood smear examination to demonstrate the parasite, were selected. Patients who had a history of systemic illnesses such as hypertension, diabetes, chronic kidney disease, tuberculosis, nephritis, chronic liver disease, acute or chronic viral hepatitis, and those on medications which would affect liver and renal function tests, were excluded.
Patients who had pneumonia, urinary tract infection and leptospirosis were also excluded. Patients who fulfilled inclusion criteria were asked about complaints such as fever, chills, malaise, bodyache, jaundice, oliguria, hematuria, swelling over body, breathlessness, bleeding tendencies, altered sensorium, convulsions etc. On admission, vital parameters like temperature, pulse rate, blood pressure and respiratory rate were recorded. Signs such as pallor, icterus, edema, bleeding were noted. Systemic examination was done to assess respiratory, cardiovascular, nervous and gastrointestinal systems. Investigations like peripheral smears, complete blood counts, platelet count, urea and creatinine, bilirubin, liver enzymes and blood sugar were done. Arterial blood gas (ABG) estimation was done in patients complaining of dyspnea. Malaria was diagnosed by gold standard method of examination of peripheral blood smear (PBS) and demonstration of asexual form of plasmodium. The PBS was made from a finger prick, thin, fixed with methanol and stained with diluted Giemsa with buffered water at pH of 7.2. It was seen under an oil immersion lens and a minimum of hundred fields were examined before declaring the PBS negative. Parasite density index was calculated for all patients being included. Severe complicated malaria was diagnosed according to the guidelines of World Health Organization.
Cerebral malaria was diagnosed when a patient had unarousable coma using Glasgow Coma Scale with exclusion of other etiologies with multiple convulsions - more than two episodes in 24 hours.[4] Renal failure, jaundice, hypoglycaemia and severe anemia were diagnosed when serum creatinine was more than 3.0 mg/dl, serum bilirubin was more than 3.0 mg/dl, random blood glucose was less than 40 mg/ dl and hemoglobin was less than 5.0 gm/dl, respectively.[4] Metabolic acidosis was labelled if plasma bicarbonate was less than 15 mmol/l. Circulatory collapse (hypotension) was defined as systolic blood pressure (BP) 30/min) with or without pulmonary edema (radiological).[4] All patients with cerebral malaria, renal impairment, ARDS were treated in the intensive care unit. Rest were managed in wards.
All forms of severe malaria and falciparum and mixed infections were treated by artesunate combination therapy and appropriate supportive therapy.[4] Statistical analysis : Data collected was systematically tabulated and analysis was done using standard statistical software SPSS version 15.0. For categorical data, chi- square test was used P< 0.05 was considered as a statistical significance at 95% confidence intervals. Multi variate analysis was done using multilinear regression analysis for various complications of falciparum malaria and outcome.
RESULTS Out of the total patients of malaria,50 % had P.vivax,35% had P.falciparum and 15% had mixed infection. Maximum patients, that is 33%, belonged to age group 21-30 years. 67% of the patients were males and 33% were females. Fever was present in 100% of patients. It was of intermittent type coming every day at an interval of 24 hours in 50% patients out of which 35 were of P. falciparum and 15 were of mixed infection. The fever was intermittent, coming every third day in 50 % patients, all of whom had P. vivax infection. Malaise and bodyache were observed in all patients. Vomiting was seen in 10 patients (10%) and malaena was reported by 5 patients (5%). 30 patients (30%) reported yellowish discolouration of sclera while 15(15%) reported decreased urine output. 13 patients (13%) presented with multiple convulsion (cerebral malaria) and 11 patients (11%) had tachypnea of more than 30 cycles per minute with saturation of oxygen below 92%. On ABG, all these patients showed acute respiratory distress syndrome (ARDS). Out of the total 100 study subjects, 53% had complicated malaria while 47% were uncomplicated cases.
Of the total patients, 23% had hypotension with a systolic blood pressure (BP) of less than 70mmHg, 78% had severe thrombocytopenia, 10% had severe anemia (hemoglobin < 5g/dl), 32% had significant jaundice (bilirubin> 3mg/dl), and 48% had renal impairment out of which 17 patients had creatinine >3mg/dl. Cerebral malaria was seen in 13% patients, ARDS in 11% patients (radiologically and on arterial blood gases) while 5 patients (5%) had metabolic acidosis (bicarbonate levels < 15mmol/l). 14 patients (14%) had a prothrombin time of >15 seconds (coagulopathy). Out of 50 patients of P. vivax malaria, 14(28%) had hypotension (systolic blood pressure below 80mmHg. Out of 35 patients of P. falciparum, 6 (17.14%) and out of 15 patients of mixed malaria, 3(20%) had hypotension (Table 1). 38 patients (76%) of P. vivax patients had severe thrombocytopenia while 27 (77.14%) patients of P. falciparum and 13 (86.66%) of mixed malaria patients had it (Table 2). 7 patients of P. vivax( 14%) had jaundice with serum bilirubin more than 3mg/dl while 15 (42.86%) of P. falciparum and 10(66.67%) of mixed malarial infection had it (Table 3).
Only 1 patient (2%) of P. vivax malaria had serum creatinine of more than 3mg/dl while 9 (25.7%) patients of P. falciparum and 7 (46.67%) of mixed infection had this level of renal impairment (Table 4). 1 patient (2%) of P. vivax malaria had severe anemia with hemoglobin(Hb) below 5gm/dl while 8 (22.86%) of P. falciparum and 1 (6.67%) of mixed infection had this low Hb. Out of 50 patients of P. vivax, 4% had prolonged prothrombin time ,while in falciparum, the figure was 0.7% and in mixed infection, the value was 0.6%. Out of 13 patients having cerebral malaria, 9 had falciparum, 3 had mixed infection and 1 had vivax infection. In the 11 patients of ARDS, 10 had falciparum and 1 had vivax infection. Among 5 patients of metabolic acidosis, 3 were of falciparum and 2 of mixed infection (Table 6). Out of 17 patients having severe renal impairment, 8 underwent hemodialysis. All patients of ARDS ,severe renal impairment and cerebral malaria were treated in the ICU. Hence, severe thrombocytopenia and jaundice were the two most common complications found in this study. P. vivax accounted for more number of patients with hypotension than the other types of malaria but this difference was not found to be statistically significant.
Also, number of patients of severe thrombocytopenia in vivax and other malarias were comparable. The rest of the complications were predictably more in falciparum and mixed infections. Interestingly, cerebral malaria and ARDS were seen in one vivax patient each. In this study, there were 90% survivors and 10% of patients succumbed. Hence, the case fatality rate was 10%. Out of 90 survivors, 43 patients (47.7%) had some form of complicated malaria, whereas all patients who succumbed (10) had complicated malaria. All 10 patients (100%) had platelet counts of 3mg/dl in 4 patients (40%). Hypotension and jaundice was present in 3 patients (30%). Severe anemia was observed in 4 patients out of 10(40%). 7 patients had cerebral malaria (70%) and 5 had ARDS(5%) (Table 6). The case fatality rate for cerebral malaria was 54% and of ARDS was 45% respectively. All forms of severe malaria were treated by artesunate combination therapy as recommended by latest guidelines of WHO.[4]
DISCUSSION The prevalence of complicated malaria has significantly increased in the last decade. Western India has been hypoendemic for malaria with certain pockets of P.falciparum.[5] With a spurt in developmental activity in this area and increased irrigation, there has been a change in clinical profile of malaria in this region. Malaria caused approximately 929 000-1 685 000 deaths worldwide in 2010.[2] Resistance of mosquitoes to insecticide and chloroquine resistance has lead to an increase in complicated malaria. Over the last many years, jaundice and acute renal failure have been increasingly noticed in patients with malaria. Severe malaria has been defined by WHO as presence of one or more pernicious syndromes in a patient with asexual forms of plasmodium species in his blood.[4] According to annual report of Government of India, 38.6% of all cases from different parts of the country were due to P.falciparum. [8] . In this study,35% of patients were positive for P.falciparum. In a study by Kochar DK et al, 58.2% of patients were positive for P.falciparum.[6] In this study,67% of the patients were males and 33% were females and majority of patients (74%) were between ages of 21-50 years. According to a study by Das et al, burden of malaria is higher in males than females. [9]
Over the last 10 years, it has been noted that clinical profile of malaria has undergone a significant change in India. The present study revealed that severe thrombocytopenia was present in 78%, jaundice and hepatic dysfunction in 62%, renal failure in 48% , hypotension in 18%, cerebral malaria in 13% ,ARDS in 11%, severe anemia in 10% and metabolic acidosis in 5%. P. vivax accounted for more patients with hypotension than the other types of malaria. Also, number of patients of severe thrombocytopenia in vivax and other malarias were comparable. The rest of the complications were predictably more in falciparum and mixed infections. According to Kochar DK et al, cerebral malaria (25.75%), hepatic involvement (11.47%), spontaneous bleeding (9.58%), hemoglobinuria (7.89%), severe anemia (5.83%), algid malaria (5.26%), ARDS (3%) and renal failure (2.07%) were the important manifestations observed in P. falciparum infections.
The overall mortality was 11.09%.[10] In another study by Kochar DK et al, complications observed in P. Vivax malaria were hepatic dysfunction and jaundice in 23 (57.5%) patients, renal failure in 18 (45%) patients, severe anemia in 13 (32.5%) patients, cerebral malaria in 5 patients (12.5%), acute respiratory distress syndrome in 4 patients (10%), shock in 3 patients (7.5%), and hypoglycemia in 1 (2.5%) patient. Thrombocytopenia was observed in 5 (12.5%) patients, and multi-organ dysfunction was detected in 19 (47.5%) patients. [6] In another study done by Naha K et al, anaemia was seen in 65 (30.5%), leucopenia in 38 (17.8%) and thrombocytopenia in 184 (86.4%) patients of P. vivax infection. Hepatic dysfunction was noted in 40% and hypoalbuminemia was observed in 157 (73.6%) cases.
Elevated serum creatinine was noted in in 59 (27.5%) patients. Overall, 107 (50.2%) patients fulfilled WHO criteria for severe malaria.[11] In this study, many patients with mixed infections presented with complications such as hypotension, thrombocytopenia, jaundice ,renal impairment and cerebral malaria. But in a study by Luxemberger C et al, severity of P. falciparum is attenuated by concomitant P. vivax infection.[12] Hence, P.vivax is no longer the benign infection it was and a high index of suspicion for its complications has to be kept by primary care physicians so that appropriate referrals can be made. Falciparum and mixed malarias are the most dangerous infections and complications involving all major organs occur in a vast number of patients and hence these should be picked up fast and managed without delay.
CONCLUSION The complications seen in this study were mainly severe thrombocytopenia , hypotension, jaundice, renal impairment, cerebral malaria, ARDS, severe anemia and metabolic acidosis; severe thrombocytopenia and jaundice being the commonest, and. P. vivax accounted for more patients with hypotension than the other types of malaria. Predictably, other complications were more in the falciparum group. But the numbers were many in the vivax group also, although not statistically significant. Mixed malaria accounted for severe complications as well.
ACKNOWLEDGEMENT The authors acknowledge the help and support received from the head of the institute and hospital superintendent, as well as all the nursing and support staff. Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.
Source of Funding : Self
Conflict of interest: no conflict of interest amongst authors
Englishhttp://ijcrr.com/abstract.php?article_id=363http://ijcrr.com/article_html.php?did=3631. Park JE, Park K. Textbook of Preventive and Social Medicine,16th Edition, 1998;188-201.
2. Murray CJL, Rosenfeld LC, Lim SS et al. Global malaria mortality between 1980 and 2010: a systematic analysis. The Lancet 2012;379(9814):413-431.
3. Gilles HM. The malaria parasites. In: Warrell DA, Gilles HM, editors. Essential malariology. Arnold; 1993. pp. 12–34.
4. WHO. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 2000;94(Suppl 1): S1-90.
5. Centre for disease control and prevention, Malaria Facts 2004
6. Kochar DK, Das A, Kochar SK,Saxena V, Sirohi P, Garg S et al. Severe P.Vivax malaria: A report on serial cases from Bikaner in Northwestern India. Am J Trop Med Hyg 2009;80(2):194-198.
7. Joseph V, Varma M, Vidhyasagar S, Matthew A. Comparison of the Clinical Profile and Complications of Mixed Malarial Infections of Plasmodium Falciparum and Plasmodium Vivax versus Plasmodium Falciparum Mono-infection. Sultan Qaboos Univ Med J. 2011 Aug; 11(3): 377–382.
8. Government of India, Annual Report 1995-96.DGHS,New Delhi
9. Das NG, Baruah I, Kamal S, Sarkar PK, Das SC, Santhanam K. An epidemiological and entomological investigation on malaria outbreak at Tamalpur PHC,Assam. Indian J Malariol 1997;34:164-170.
10. Kochar DK, Kumawat BL,Karan S, Kochar SK, Aggarwal RP et al. Severe and complicated malaria in Bikaner, Rajasthan,Western India. Southeast Asian J Trop Med Public Health 1997;28(2):259-267.
11. Naha K, Dasari S, Prabhu M. Spectrum of complications associated with P. Vivax infection in a tertiary hospital in SouthWestern India. Asian Pacific Journal of Tropical Medicine 2012; 5(1): 79-82.
12. Luxemburger C, van Vugt M, Jonathan S, McGready R, Looareesuwan S, White NJ, Nosten F. Treatment of vivax malaria on the western border of Thailand. Trans R Soc Trop Med Hyg. 1999;93(4):433-8.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareNUTRIGENOMICS IN PERIODONTICS- AN OVERVIEW
English3135R. Svedha PriyadharshiniEnglish R. VijayalakshmiEnglish N. AmbalavananEnglish T. RamakrishnanEnglish Anitha LogaranjaniEnglishNow that we have entered the postgenomic era, the association between the potential protective role of nutrients and periodontal diseases is well established. It is likely to know that interactions between the genotype and diet are important in determining periodontal disease risk. A change in dietary pattern represents a promising approach in reducing the risk of aging by modulating gene expression. One of the most practical applications of nutritional modulation of chronic disease is that they regulate the expression of key inflammatory genes. Nutrigenomics is a branch of nutritional genomics focusing on identifying and understanding molecular- level interaction between nutrients and other dietary bioactives with the genome. New techniques and knowledge from the Human Genome Project named as nutrigenomics are currently combined with already established scientific disciplines such as pharmacogenomics and toxicogenomics. This manuscript reviews the evidence for nutritional exposures in the etiology and makes recommendations for daily nutritional intake for periodontal prevention / treatment regime.
EnglishNutrigenomics, Nutrition, Periodontics, PharmcogenomicsINTRODUCTION
Periodontitis, involving local microbial challenge and host responses, is an irreversible condition characterized by the destruction of tooth supporting tissues, periodontal ligament, alveolar bone and cementum, eventually resulting in a tipping of the bone-remodeling balance in favor of bone resorption and tooth exfoliation. It is widely regarded as the second most common disease worldwide, after dental decay and in the United States has a prevalence of 30-50% of the population, but only about 10% have severe forms.[1] There is an abundance of both empirical evidence and substantial theoretical justification for accepting the widespread belief that periodontal diseases have more than one cause i.e. they are of multifactorial etiology and complex in nature.[2] Susceptibility to periodontal diseases involves the interplay between genetic, bacterial, environmental and nutritional factors. Common dietary chemicals act on the human genome, either directly or indirectly, to alter gene expression or structure. Genes are important in determining the function, but nutrition is able to modify the degree of gene expression. Some individuals who are overtly healthy as they reach young adulthood will begin to experience the complications of chronic diseases such as cardiovascular disease, arthritis, osteoporosis, and Alzheimer’s disease, whereas others will reach their 80s with minimal evidence of these debilitating conditions. This simple observation defines much of the future focus of the health care delivery system and the search by individuals for prolongation of healthy and productive lives. During our lifetime, nutrients can modify physiologic and pathologic processes through epigenetic mechanisms that are critical for gene expression.
History
• On 1st April 1869, the first isolation of DNA was made by Friedrich Miescher.
• On 25th April 1953, Watson and Crick published “the molecular structure of DNA”.
• In 1997, the first nutrigenomics company was launched
. • In 1999, the name nutritional genomics was changed to genomics by Nancy Fogg-Johnson and Alex Merolli which provides powerful means of discovering hereditary factors in disease.
If the genomic era was said to have a precise birth date, it was on April 14, 2003. That was when Human Genome Project[3] was launched with the participation of former U.S President Bill Clinton and former British PM Tony Blair which contained the complete sequencing of the human genome. It was then realized that a new era in biological and medical sciences was beginning. This is often referred to as the ‘omics’-revolution.
• In 2004, NuGo (European Nutrigenomics Organization) was born and funded until June 2010.
• In 2007, Nestle Research Center joined the industrial platform of the Kluyver Centre for Genomics of industrial fermentation, Netherlands.
• In 2008, US Berkeley scientist predicted human genome tests within five years for $100.
Practical Applications of Nutrigenomics[4]
1. Genes and proteins expressed differentially in health and disease that are modifiable by nutrients are identified.
2. Genes, proteins, and metabolites are influenced by specific nutrients that are known to be beneficial or harmful are identified. a. To identify genes, proteins, and metabolites that are altered by dietary fats associated with cardiovascular disease. b. To identify genes, proteins, and metabolites that is altered by omega 3 fatty acids.
3. Genetic variations that alter the nutrient– gene interactions in applications 1 and 2 are identified.
Evolutionary Eating: Caveman Diet to Junk
From the Paleolithic era up to the Neolithic period, approximately 10,000 years ago, man was a nomad who lived by hunting and picking wild fruits and vegetables and his diet was basically made up of game (protein and lipids) as well as wild berries, vegetables and roots (carbohydrates with low glycemic index and high fiber content). Wherein in the modern era people consume high calorie diet that lead to plethora of health problems.
Target Gene Mechanism versus Signature Profile Biomarkers One of the main applications in nutrigenomics research relates to health and prevention of chronic diseases (such as e.g., cardiovascular diseases, periodontitis, metabolic syndromes, cancer, etc) through diet. Also these disorders are multifactorial in origin and the loss of biological homeostasis maintenance and altered biochemical composition of cells can be primary cause in disease. So there is a need to understand the molecular mechanisms that describe homeostasis at biochemical, cellular and organ levels associated with the healthy and diseased states. As a result, there is a need for molecular biomarkers that allow early detection of the onset of disease or, ideally, the pre-disease state.
These early effect biomarkers should accurately reflect subtle changes in homeostasis and the efforts of the body to maintain it. However, the discovery of such biomarkers is not easy since dietgene interactions are complex. Unlike the comparative simplicity of the single-gene disorders, chronic diseases are likely the result of multiple genes and multiple variants of each gene interacting with multiple environmental factors, each combination making a relatively small contribution to overall homeostasis, function and health. Thus, to determine health status and reflecting the functional response to a bioactive food component, complete biomarker profiles of gene expression, protein expression and metabolite production will be more useful than single markers.
To do this, the availability of advanced analytical techniques will be essential for the investigation of complete biomarker profiles of gene expression, protein expression and metabolite production. It is well known that interleukin-1 gene polymorphisms are associated with severe periodontitis. Studies in nonhuman primates have shown that drugs that specifically block IL-1 and TNF-α dramatically and significantly reduce the tissue destruction even when the bacterial challenge is not reduced. It is shown that persons with IL-1 genotype are consistent with haplotype-1, i.e carriage of allele 2 at both IL-1A (-889) and IL-B (+3953), had an increased risk of severe periodontitis.[5] Since then 17 studies have been published that had evaluated the association of IL-1 genotypes with severity of periodontal disease in white adults.[6]
Fourteen of those reported statistically significant associations, whereas three failed to show association between IL-1 gene variation and the severity of periodontal disease. It is well established that certain nutrients have direct effects on gene expression through both epigenetic mechanisms and modification of transcription factors.[7] Polyunsaturated fatty acids (PUFAs) are one such example of nutrients that directly alter transcription factors through the nuclear peroxisome proliferator activated receptors (PPARs). These receptors bind to fatty acid ligands and then form a heterodimer complex with another nuclear receptor, retinoid-X- receptor.
This heterodimer complex binds to specific DNA sequences to regulate gene expression. PPAR activation has been shown to modulate inflammation, including the inhibition of secretion of IL-1, 6, TNF-α by stimulated monocytes.[8] Other nutrients alter the oxidation–reduction status of the cell to indirectly influence transcription factor activity. Many antioxidants will alter the activation status of the transcription factor nuclear factor κB, which is a key regulator of many genes.
Dietary Signatures
• Act as ligands for transcription factor receptors
• Be metabolized by primary or secondary metabolic pathways thereby altering concentrations of substrates or intermediates.
• Alter signal transduction pathways at the level of proteins, enzymes, metabolites- cell function. Nutrients function as signals that are detected by sensory system in our body which interpret information from nutrients about dietary environment including transcription factor, change in gene, protein expression, metabolite production that specifically target the biological activities that are influenced by variations in key inflammatory genes and offer greater potential to modulate the clinical expression of some chronic diseases. Also different diet can produce different signal pattern.
Epigenetics It can be defined as somatically heritable states of gene expression resulting from changes in chromatin structure without alteration in the DNA sequence, including DNA methylation, histone modifications and chromatin remodeling.[10] Epigenetic modifications can be carried out by altering external or internal environmental factors and have the ability to change gene expression. In the past, epigenetics was focused on embryonic development, aging and cancer. Presently, epigenetics is exceptionally important, because nutrients and bioactive food components can alter the expression of genes at the transcriptional level. Folate, vitamin B-12, methionine, choline, betaine can affect DNA methylation and histone methylation. In recent years, epigenetics has become an emerging issue in broad range of diseases such as type 2 diabetes, obesity, periodontal diseases and neurocognitive disorders. Studies that highlight the importance of interactions between genotype and diet in determining the risk of diseases.
• Individuals homozygous or heterozygous for a particular single nucleotide polymorphism in the estrogen receptor gene, and who consumed higher amounts of phytoestrogen and isoflavone was shown to have reduced prostrate cancer risk (57% and 27%).[11] (Chang et al 2006)
• No association was found between soy diet and cancer risk in subjects who are homozygous to a wide type allele. But individuals carrying a variant of Nacetyl transferase 2 gene and consumed high amount of cooked red meat was shown to have risk of colon cancer.[12] (Hein et al DW 2002)
• Low dietary intake of PUFA and polymorphism of transcription factor had high levels of plasma triglyceride levels and low levels of high density cholesterol. [13] (Low et al 2007)
Micronutrients in Gene Expression Common chronic diseases are complex in their biochemical processes, and many of these diseases have strong genetic influences that explain a significant part of the variance in the clinical expression of the disease. • However, it is almost certain that some genes will have more of an influence than others on the future course of a disease and on the effects that specific nutritional compounds have on overall health. Diseases arise because of genetic predispositions to one or more of these stressors such as psychological stress, inflammatory stress, oxidative stress, metabolic stress. Nutrigenomics represents a major effort to improve our understanding of the role of nutrition and genomic interactions in at least the first three of these areas.
The role diet plays in the development and progression of dental caries has been well characterized in the literature, but the importance of nutrition as a predisposing factor for the development of periodontal disease is not well defined. Recently it has been suggested that nutrition is important in redressing the balance between microbial challenge and host response because it is implicated in a number of inflammatory diseases and conditions.[14] (Vander Velden 2011) Increase in oxidative stress is antagonized by a complex system of antioxidants which include antioxidant vitamins. However it has been demonstrated that the most important small molecule antioxidant species is glutathione. Glutathione exists in both oxidized (GSSG) and reduced (GSH) forms. Specific nutrients (antioxidant vitamins A, C, E) and trace element selenium, copper, zinc can modulate the immune and inflammatory responses that maintain epithelial cell integrity and structure. The nutrients get depleted during inflammation with generation of Reactive Oxygen Species (ROS) causing damage to the cellular tissues.[15] (Hornig 2007).
Moreover, selenium has further important redox functions, with selenium-dependent glutathione enzymes being involved in the reduction of damaging lipid and phospholipid hydroperoxides to harmless products. Vitamin C acts as a powerful scavenger of free radical. The association between low intake of vitamin C and occurrence of periodontitis has been demonstrated, in a study by Nissada 2010.[16] Vitamin E terminates free radical chain reaction, stabilizes membrane structure. It is shown to have mitigatory effects on inflammation and collagen breakdown. A low level of vitamin E in gingival tissues of periodontitis patients has been reported. (Offenbacher 1990)[17] Omega 3 fatty acids such as n-3 PUFA (oily fish), increase the tissue concentration of eico-sapentaenoic acid, decosahexaenoic acid and down-regulate inflammation and inhibit bone loss in vitro. (Sun et al 2003)[18]
DISCUSSION Nutrigenomics and Periodontics It has also been reported that the n-6 PUFA levels in the serum are higher in periodontitis patients, suggesting that an imbalance between n-6 and n-3 fatty acids may contribute to susceptibility to oral bone loss.[18] (Requirand et al 2000) The main functional value of pomegranate in oral health is its polyphenolic flavonoid content. The components of pomegranate juice were found to significantly inhibit cytokine IL-8, PGE2 , nitric oxide, human salivary α-amylase, α- glucosidase activity and found to reduce aspartate aminotransferase activity in saliva. The hydro-alcoholic extract from pomegranate fruit has shown to decrease the Colony Forming Unit (CFU) per milliliters of dental plaque by 84%. Local action and topical effects of antioxidant agents from pomegranate on the oral tissues have been hypothesized to have preventive effect against diseases of the oral cavity. One minute rinsing with a mouthwash containing pomegranate extract successfully reduced the amount of microorganisms cultured from dental plaque.[19] (Di Silvestro RA 2009). The seeds of Garcinia mangostana are reported to contain vitamin C.
A composition in the form of a biodegradable gel, chip or ointment is provided for the treatment of periodontitis, comprising an antimicrobial or antibacterial activity against periodontal pathogen and forms a liquid crystal structure on contacting gingival fluid, which releases active ingredients gradually, to provide a sustained release dosage form. The effect of Morinda citrifolia L. fruit juice significantly mitigated the gingival inflammation. The combination ofDISCUSSION Nutrigenomics and Periodontics It has also been reported that the n-6 PUFA levels in the serum are higher in periodontitis patients, suggesting that an imbalance between n-6 and n-3 fatty acids may contribute to susceptibility to oral bone loss.[18] (Requirand et al 2000) The main functional value of pomegranate in oral health is its polyphenolic flavonoid content. The components of pomegranate juice were found to significantly inhibit cytokine IL-8, PGE2 , nitric oxide, human salivary α-amylase, α- glucosidase activity and found to reduce aspartate aminotransferase activity in saliva. The hydro-alcoholic extract from pomegranate fruit has shown to decrease the Colony Forming Unit (CFU) per milliliters of dental plaque by 84%.
Local action and topical effects of antioxidant agents from pomegranate on the oral tissues have been hypothesized to have preventive effect against diseases of the oral cavity. One minute rinsing with a mouthwash containing pomegranate extract successfully reduced the amount of microorganisms cultured from dental plaque.[19] (Di Silvestro RA 2009). The seeds of Garcinia mangostana are reported to contain vitamin C. A composition in the form of a biodegradable gel, chip or ointment is provided for the treatment of periodontitis, comprising an antimicrobial or antibacterial activity against periodontal pathogen and forms a liquid crystal structure on contacting gingival fluid, which releases active ingredients gradually, to provide a sustained release dosage form. The effect of Morinda citrifolia L. fruit juice significantly mitigated the gingival inflammation.
The combination of good oral hygiene and administration of this juice was a promising treatment for gingivitis and periodontitis because of its strong anti-inflammatory effects. Results from a prospective, observational study carried out over 14 years revealed that men with high consumption of wholegrain were 23% less likely to develop periodontitis.[20] (Merchant 2006) A recent randomized double blind clinical trial investigated the potential clinical benefits of a powdered fruit and vegetable juice concentrate on the treatment of patients with chronic periodontitis and showed that there was increased pocket depth reduction following standard non surgical therapy compared to a placebo group.15 (Vander Veldon 2011)
• Research studies using an experimental gingivitis model have shown increased levels of bleeding on probing when participants were fed with a diet high in carbohydrates when compared to those on a low sugar diet.[21] (Ashley 1984)
• This finding has been further supported by a study investigating volunteers placed on a primitive diet which was high in fibre, anti-oxidants, and fish oils, but low in refined sugars and with no oral hygiene measures. [22] (Robinson 2000)
As would be expected plaque levels increased significantly and classic periodontal pathogens emerged within the biofilm, but unexpectedly gingival bleeding significantly reduced from 35% to 13%. A rodent model of zinc deficiency has shown to have an increased susceptibility to periodontal disease progression, as revealed by increased plaque and higher gingival index measurements. As an example of the potential of nutrigenomics tool for assessing the role of nutrition in periodontal disease, the role of the micronutrient zinc, a zinc transporter gene and the risk of developing type 2 diabetes was investigated. Recent genome-wide association studies have identified a genetic-susceptibility locus for type 2 diabetes comprising a nonsynonymous single nucleotide polymorphism (C ⁄ T; rs13266634) in a β cell-specific zinc-transporter gene.
This zinc transporter gene (SLC30A8, coding for ZnT8) may be important in insulin storage and release. [23, 24, 25] In light of this new finding, the existing knowledge that zinc has a specific role in beta cell function takes on new significance with respect to potential strategies to prevent or treat type-2 diabetes and potentially periodontal disease. The recommendations of 2011 European Workshop on Periodontology suggested that the dental team should consider including fish oils, fibre, fruits and vegetables and to reduce levels of refined sugars as part of a periodontal prevention / treatment regime and a general health benefit message.[26] (Chapple et al 2012)
CONCLUSION Nutrigenomics is the combination of molecular nutrition and multi-Omics applications. There is not one gen-Omics tool that can “do everything”. One of the goals of applying genomics and proteomics technologies to nutritional science is to match individuals and specific nutrients to achieve special health benefits. Nutritional products that specifically prevent the negative effects of pro-inflammatory genetic variations may represent excellent preventive agents that would benefit large segments of the population. The current literature on the relationship between diet and periodontal disease is largely inconclusive; this is most likely due to a lack of clarity in assessment of nutritional status.
Over the last few years improved understanding of ways to assess and investigate nutritional status has emerged along with the recognition of the importance of assessing nutritional intake, body composition and biochemical measures of nutrition. A second multi-centre follow up study is currently in progress aiming to determine the effects of supplementation upon periodontal inflammation prior to periodontal treatment. Further studies are needed to better understand the use of nutrients or bioactive food components for maintaining good health and preventing periodontal disease through modifiable epigenetic mechanisms.
ACKNOWLEDGEMENT Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.
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5. Kornman KS, Crane A, Wang HY, di Giovine FS, Newman MG, Pirk FW et al. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997;24(1):72-77.
6. Lopez NJ, Jara L, Valenzuela CY et al. Association of interleukin-1 polymorphisms with periodontal disease. J Periodontol 2005;76(2):234-243.
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8. Ricote M, Li AC, Wilson TM, Kelly CJ, Glass CK. The peroxisome proliferator- activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391(6662):79-82.
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11. Hedelin M, Balter KA, Chang ET, Bellocco R, Klint A, Johansson JE et al. Dietary intake of phytoestrogens, estrogen receptor β polymorphims and the risk of prostate cancer. Prostate 2006;66(14):1512-1520.
12. Ishibe N, Sinha R, Hein DW, Kulldorff M, Strickland P, Fretland AJ et al. Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas. Pharmacogenetics 2002;12(2):145–150.
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15. Semba RD, Tang AM. Micronutrients and the pathogenesis of human immunodeficiency virus infection. Br J Nutr 1999:81(3):181–189.
16. Vander Veldon U, Chapple IL, Kuzmanova D. Micronutritional approaches to periodontal therapy. J Clin Periodontol 2011;38 suppl 11:142-158.
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18. Vedin I, Cederholm T, Freund Levi Y, Basun H, Garlind A, Faxen Irving G et al. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: The Omeg AD study. Am J Clin Nutr 2008;87(6):1616–1622.
19. Di Silvestro RA, Di Silvestro DJ. Pomegranate extract mouth rinsing effects on saliva measures relevant to gingivitis risk. Phytother Res 2009;23(8):1123-1127.
20. Merchant AT, Pitiphat W, Franz M, Joshipura KJ. Wholegrain and fiber intakes and periodontitis risk in men. Am J Clin Nutr 2006;83(6):1395–1400.
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22. Baumgartner S, Imfeld, T, Schicht O, Rath C, Persson RE, Persson GR et al. The impact of the stone age diet on gingival conditions in the absence of oral hygiene. J Periodontol 2009;80(5):759–768.
23. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007;316(5829): 1341–1345.
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25. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007;316(5829):1336–1341.
26. Chapple ILC, Milward MR, Ling-Mountford N, Weston P, Carter K, Askey K et al. Adjunctive daily supplementation with encapsulated fruit, vegetable and berry juice powder concentrates and clinical periodontal outcomes: a double blind RCT. J Clin Periodontol 2012;39(1):62-72.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareSTUDY ON THE IMPACT OF DRUGS ON HEART AND CARDIO-VASCULAR SYSTEM IN CRABS
INHABITING FRESHWATER, MARINE AND BRACKISH WATERS
English3645Premraj LoganathanEnglish M. Ranjani Devi and Dr. J.M.V. KalaiarasiEnglishAim: The present study was aimed to evaluate the effects of various drugs on different in habitat crabs Methods: The sterile syringes was loaded with different chemicals and poured over the heart of the dissected animal. The stop watch was switched on again and the number of beats per minute was noted. The rate of heart beats was plotted in relation to time exposure in four chemicals like Adrenaline, Atropine, Ephedrine and Ringer solution. The plotted graphical interpretation has been given the nature of chemical and their intensity and finally removed the hearts from the treated animal were subjected to histopathology and haemolymph preparations. Results: The hearts of the three different crustaceans were isolated for the histopathology process to study, diagnose and to differentiate between the cardiac muscles of the crabs. It was observed that edema was seen in all the smears but it was higher in marine species than the estuarine and freshwater species. Inflammation was also seen but except marine species, the others show inflammation. There were no toxic accumulation and pathogens observed and haemolymphs was observed that the smears were even and contains many cells which are irregular in their shape and size. Conclusion: From the results of study we conclude that, Adrenaline, Atropine, Ephedrine and Ringer solutions initially inhibit the heart rate which indicates animal try to settle-down into the chemical medium but later on the effects of toxicants accelerate the metabolic activity of the animals which accelerate the rate of heart beat in a crab after this treatment. Then the heart rate slowly decreases as the animal dies.
EnglishCarcinusmaenas, Scylla serrata, Parathelphusapantherina, Histopathology and haemoloymphINTRODUCTION
Crustaceans possess an open type of circulatory system and the haemolymph flows in the blood sinuses. A dorsally situated heart is present in most of the crustaceans. Data available on the rate of heart beat in crustaceans suggest that the heart rate is influenced by a number of factors like body size , activity, respiration, stress, light, blood composition, temperature , nutritional status, population density, amount and the kind of food, oxygen and carbon dioxide content of medium, moulting, diurnal cycle, PH, internal pressure etc. By far the best studied factor that influences heart beat rate is body size. As a general rule, it might be stated that the heart rate varies inversely with body size. Thus the rate of heart beat is faster in smaller animals of a species and slower in larger species.
The Q10 of the rate of heart beat is affected by sex is shown long time before and it might also mean that the rate of heart beat is different in the two sexes. Effects of different heavy metals on biochemical constituents in fishes and other aquatic animals is the current topic of interest, probably because of the contamination of natural water resources by these pollutants from various industrial effluent disposals, threatening the fish culture and population. Action of pesticides, heavy metals is stress on the non-target organisms which induce the changes in them. Any changes to come over the stress needs energy, normally various sources of energy metabolism are acquainted by the organisms to encounter the stress. The haemolymph or blood is an important tool of transport of these constituents therefore the study of haematological changes in the organism under stress induced by various pollutants assumes importance.
The paucity of information has become particularly apparent in recent years as investigators have become interested in the cardiovascular system of crab with considerable success. The heart rate of marine, estuarine and fresh water crabs during aquatic and aerial respiration was studied. Recently valuable contribution has been studied the effect of three chemicals, viz. Adrenaline, Atropine and Ephedrine on the heart rate of these crabs. Studied effect of Adrenaline, Atropine and Ephedrine on the isolated hearts of Carcinusmaenas, Scylla serrata and Parathelphusapantherina. In recent year investigators divert their concentration to observe effect of toxicant such as insecticide, heavy metals, drugs and antibiotics upon such sensitive physiological system of different animals. The present study was undertaken to determine the effect of three drugs such as Adrenaline, Atropine and Ephedrine on the heart rate of freshwater, estuarine and marine crabs.(Arunaet al., 2011). Crustaceans possessing many primitive features tend to have myogenic hearts, although neurogenicity is dominant in the more advanced malacostracan groups (Wilkens, 1999a; Yamagishi et al., 2000) and possibly members of the Ostracoda. Exactly how the heart is regulated, via neuronal and neuro-hormonal controllers, has recently been investigated and there is a long history of examining the effect of environmental factors (e.g., hypoxia, salinity) on aspects of cardiac function (McMahon, 1999a, 2001; De Pirroet al., 1999).
The animals required food and oxygen continuously for energy and to perform various metabolic activities. Thus digested food and oxygen should be transported to all the cells. This function is carried out with the help of body fluids. The arthropods possess the open type of circulatory system, which is presumably derived from the highly organized closed system of their annelids or pre-annelids ancestors. In most of the crustaceans the heart is dorsally placed inside the body. Whatever knowledge about cardio physiology of the crab does not fulfill the existing gap. Now-a-days investigators divert their concentrations to observe effects of toxicants pesticides upon the sensitive physiological system of animals. (Deshai R. B, Shinde V. D, Katore B. P, et al., 2012). The following experiments, which include a study of the action of certain drugs and autacoids upon the hearts of crabs, were undertaken as a preliminary to a reinvestigation of the nervous supply to the crustacean heart and its relationship to the heart-beat.
The results obtained are of interest in view of the paucity of our knowledge regarding the effects of such substances on the heart of invertebrates. Since the investigation of the action of adrenaline and ephedrine formed the starting-point of the present study, the literature relating to this subject will first be dealt with, other work being noted and references given as the occasion arises. It would seem that Carlson was the first to record a positive action of adrenaline on the heart of an invertebrate, observing an excitatory effect on both the cardiac ganglion and myocardium of a marine crab, but giving no graphic record of his experiments. Elliot obtained negative results in a single experiment on the crayfish, in which he dropped adrenaline on to the surface of the exposed heart without effect. He does, however, state that “movements of the animal followed as the drug was carried round in the circulation and irritated the nervous ganglia,” this being observed also by Brucke and Satake in an experiment on Homarus, a rise in bloodpressure and increased heart-rate (following an initial fall in blood-pressure after an injection of adrenaline) coinciding with the commencement of these movements.
More recently Hogben and Hobson have studied the action of adrenaline on a wide selection of invertebrate preparations, the Crustacea being represented by the decapods Cancer maenus. In the isolated heart of this animal, perfused with artificial seawater of suitable reaction, these authors recorded an increase in tone of the heart-muscle accompanied by acceleration of the beat in response to adrenaline in a concentration of 1 in 40,000 parts of the perfusing fluid. They state that the latent period between the addition of the autacoid and the onset of the characteristic response was usually somewhat protracted, a minute at least intervening in most experiments, and they consider this evidence that the heart-muscle absorbs the autacoid slowly. Epinine was found by these workers to produce an effect similar to that obtained with adrenaline, but was effective in much greater dilution. (W. A. Bain et al., 1929).A drug may cause paralysis by depressing the motor nerve endings or by paralyzing the central nervous system. My results go to show that the primary action of adrenaline, atropine and ephedrine in arthropods is on the central nervous system and the peripheral ganglia and not on the motor nerve endings in the muscle.
The action on the nerve centers is a primary stimulation followed by temporary or permanent paralysis if the dose is of sufficient strength. The stimulating action of curare on the nerve centers appears immediately on the application of the solution. In the squid the stimulation results in spasms and tetanus. The primary stimulation is less in evidence in the crustaceans. In the gastropods it appears in prolonged and extreme contraction of the body muscles. In all the animals studied the stimulation of the motor nerves causes contraction of the skeletal and visceral muscles after a dose of curare that completely paralyzed the central nervous system. Atropine appears to paralyze motor nerve endings to smooth muscles (example: lungs, gastrointestinal tract) in vertebrates.
The body muscles of arthropods are of the transversely striated type, but the muscles of mollusks approaches more closely to the smooth variety. The experiments on several classes of mollusks with a view of paralyzing the motor nerve endings in the muscle by atropine have yielded uniformly negative results. So far, then, we know of no drugs that will paralyze the motor nerve endings in invertebrates without materially depressing the muscle itself, after previous paralysis of central ganglia. (A. J. Carlson et al., 1922). The neurotransmitter candidates for the intrinsic and extrinsic heart neurons have been identified in a few species for pharmacological and immunecytochemical studies. Dealing with the decapods, Yazawa and Kuwasawa (1994) proposed that gamma- amino - butyric acid (GABA) and dopamine (DA) are the extrinsic neurotransmitters of the cardio-inhibitory and cardio-accelerator nerves, respectively, in the hermit crab Aniculusaniculus. They also proposed that acetylcholine and dopamine are the intrinsic neurotransmitters of the small and large neurons, respectively, in the cardiac ganglion of that species. (Hiroshi Ando, Kiyoaki Kuwasava et al., 2004).
Atropine is the drug of choice for treatment of organophosphate nerve agent and insecticide intoxication and has been used for this indication for several decades. Adverse reactions to atropine may occur, and are of two types: toxic and allergic. Atropine is considered the drug of choice for nerve agent intoxication, since the late 1940s. It continues to be the standard treatment despite the fact that many cholinergic blocking substances have since been tested and found active. Atropine is a competitive inhibitor of the muscarinic acetylcholine receptor. It blocks the effect of excess acetylcholine and protects the receptor from further stimulation. It has a minimal effect at nicotinic receptor sites. Although atropine does not readily cross the blood-brain barrier, the drug has some central beneficial effects in OP poisoning. The central nervous system effects observed in atropine overdose demonstrate that it is capable of crossing the blood-brain barrier to some extent.
Atropine systemic toxicity causes tachycardia, tachypnea, elevated body temperature, and CNS stimulation marked by restlessness, confusion, psychotic reactions, delirium and occasionally seizures. A rash may appear on the face or upper trunk. In severe intoxication, central stimulation may cause CNS depression, coma, circulatory and respiratory failure, and death. (Eyal Robenshtok MD, Shay Luria MD, Zeev Tashma et al., 2002). The first reported use of ephedrine was in China over 5000 years ago as a drug called Ma-huang (meaning astringent yellow). It was mentioned in herbal books as early as 2000 BC. A Chinese medical plant publication in 1596, recommended the drug for improving bad circulation, reducing fever, and treating respiratory ailments. The main ingredient in the Ma-huang was dried green leaves and shoots from Ephedra sinicra.
It is now known that of the 45 species in the Ephedra genus only 25 contain the alkaloid, which can be present in leaves at concentrations of 1-2 %. Today Ephedrine is prepared by synthesis via the reductive amination of Phenyl acetyl carbinol (PAC), which is produced by Saccharomyces cerevisiae during the fermentation of sugar medium containing benzaldehyde. (Aidan J Mullen GRSC MISI et al., 1991).
MATERIALS AND METHODS
SPECIMEN COLLECTION
Young specimens of Carcinusmaenas, Scylla serrataand Parathelphusapantherina were selected for the experiment. The marine and estuarine crabs were bought from Chindadripet market, Chennai and freshwater crabs from Chengalpet in Chennai, Tamil Nadu and were transported to the laboratory in large plastic containers filled with beech water and lake water to minimize stress and mortality. They were acclimatized to standard laboratory conditions for 15 days in de-chlorinated water contained in a large aquarium with proper aeration. Cannibalism was observed during the period of acclimatization.
DIET AND FEEDING
During acclimatization period, crabs were fed with freeze dried tubifex worms in the form of small cubes and also with small pellets once daily. The pellets are composed of the following ingredients (white fish meal, shrimp meal, wheat flour, corn meal, yeast, enzyme, calcium, magnesium, biotin, vitamin A, C, E and other trace elements. Feeding was withheld for 24 hours prior to the commencement of the experiment to keep the experimental animal more or less in the same metabolic state.
REQUIREMENT OF CRABS FOR EXPERIMENT:
After acclimatization, crabs with an average weight of 20 - 50 grams were selected. The crabs were introduced into big plastic tubs which were washed thoroughly. Crabs belonging to both the sexes were used.
CHEMICALS USED:
In the present study, Adrenaline, Atropine, Ephedrine and Ringer solution were used to study its effects on the cardio system of crabs.
RINGER SOLUTION:
The crab ringer prepared had following composition. Sodium chloride: 16.100 gm, Potassium chloride :0.4162gm, Calcium chloride : 0.3403 gm, Magnesium chloride : 0.0804 gm, Sodium sulphate : 1.5261 gm, Sodium Phosphate (Tribasic) : 0.0358 gm, Glucose : 0.6000 gm, and Distilled water : 1000 ml ) The pH of the solution was adjusted to 7.7 by adding 10-15 ml. of pH 7.7 tribuffer. Suitable amounts of glucose were added to the ringer just before use. The ringer when kept in cold could be used up to 15 days. This ringer was found quite satisfactory and the heart maintained a constant beat for considerable time. Frequent changing of the fluid also enhanced the viability of preparation.
METHOD OF DISSECTION
The limbs having been removed, an opening is made on the dorsal aspect of the cephalo-thorax and a large circular portion above the cardiac region excised with the aid of bone forceps, care being taken to separate the chitinous covering from the subjacent pigmented dermis. The latter is then dissected off, the roof of the pericardium removed, and the pericardial cavity flushed out with the perfusing fluid (double distilled water). The heart beat was seen visually. The stop watch was switched on for a minute and the heart beat was noted as control.
A syringe was loaded with the chemical Adrenaline and poured over the heart of the dissected animal. The stop watch was switched on again and the number of beats per minute was noted. Two more reading were taken and average value of three observations was used for calculating the rate of heart beat expressed in terms of No. of heart beats/seconds. The same procedure was repeated for Atropine, Ephedrine and Ringer solution. The heart beat was tabulated and the concordant values were found for each chemical separately. The rate of heart beats was plotted in relation to time exposure in four chemicals like Adrenaline, Atropine, Ephedrine and Ringer solution. The plotted graphical interpretation has been given the nature of chemical and their intensity and finally the hearts of all treated animal were subjected to histolopathology and haemolymph preparation.
HISTOPATHOLOGY
SOLUTIONS USED
10% Neutral Buffered Formalin and Bouin’s Solution - Fixation: Bouin’s Solution fixed tissue sections must be thoroughly washed in running tap water until all the yellow color (the picric acid) is removed from the tissue. Failure to remove the Bouin’s Solution can result in inadequate staining. Staining problems have been particularly noticed in Immuno-histochemistry staining. Xylene: Deparaffinization : Removal of paraffin from tissue sections. Clearing: Removal of alcohol from tissue section (miscible with permount for coverslipping) 100% Alcohol, Reagent or Absolute (200 proof): Hydration: Removal of xylene from tissue sections and down a gradual series to distilled water. De-hydration:Removal of water from the tissue sections through a graded alcohol to xylene.
95% Alcohol
Alcohol, Reagent 95.0mls 50.0mls 190.0mls Distilled Water 5.0 mls 950.0 ml 3610.0 mls
METHODS: TISSUE ACQUISITION AND PREPARATION:
Heart was carefully removed from three kinds of crabs and placed in a labeled specimen cup containing approximately 75 mls of 10% Formaldehyde in phosphate buffer. The tissues are allowed to fix overnight at room temperature before they are handled. The following day, the tissues are examined and the heart is bisected before all three tissues are placed in labeled cassettes prior to automated processing. They are then bisected at their mid-point to insure that sections will be taken from an anatomically consistent level. The cassettes are returned to the 10% Formaldehyde solution and are held under house vacuum for a minimum of three days until they are ready to be loaded into the automatic tissue processor.
TISSUE PROCESSING: The cassettes are placed in the Microm HMP 300 and processed at room temperature, except where noted, according to the following automated protocol:
Step 1: Fixed in 10% Formaldehyde for 1 hour.
Step 2: Fixed in 10% Formaldehyde for 1 hour.
Step 3: Dehydrated in 50% Ethanol for 45 minutes.
Step 4: Dehydrated in 70% Ethanol for 45 minutes.
Step 5: Dehydrated in 95% Ethanol for 45 minutes.
Step 6: Dehydrated in 95% Ethanol for 45 minutes.
Step 7: Dehydrated in 100% Ethanol for 1 hour.
Step 8: Dehydrated in 100% Ethanol for 1 hour.
Step 9: Cleared in Xylene for 1 hour.
Step 10: Cleared in Xylene for 1 hour.
Step 11: Infiltrated with Tissue Prep II paraffin for 1.5 hours at 60°C, under vacuum.
Step 12: Infiltrated with Tissue Prep II paraffin for 2.5 hours at 60°C, under vacuum.
Step 13: Infiltrated with Tissue Prep II paraffin for 4.0 hours at 60°C, under vacuum.
TISSUE SECTIONING: Three-micrometer thick sections are cut from each tissue on a Microm HM355S microtome. Six slides are produced for each tissue. Tissue sections are mounted on silanized/charged slides with the exception of one uncharged slide dedicated to the Jones Silver Stain. Heart slides carry three section. One slide is stained with Gomori’s One-Step Trichrome for immediate documentation. The rest are held in reserve for future investigation.
TISSUE STAINING: Once all the samples are cut, one slide from each tissue is processed according to this procedure.
Note: Steps 1-10 and 21-28 are performed on the Sakura DRS 2000 Automatic Stainer.
Deparaffinization
1. Xylene, 5 minutes
2. Xylene, 4 minutes
3. Xylene, 3 minutes
4. Xylene, 2 minutes Hydration
5. 100% Alcohol, 2 minutes
6. 100% Alcohol, 2 minutes
7. 95% Alcohol, 1 minute
Rinsing
8. Distilled Water, 1 minute
9. Distilled Water, 1 minute
10. Distilled Water, 1 minute
11. Remove slides from the Sakura Stainer and place in a Tissue Tek ‘White’ staining dish containing fresh distilled water.
Pre-treatment - Mordant: Mandatory: Under a Hood
12. Place slides in the pre-warmed 60 °C Bouin's Solution and incubate at 600 C for 60 minutes (Optional: Bouin’s Solution overnight at room temperature)
13. Remove slides from Bouin’s and place in tap water.
Washing
14. Wash well in running tap water until all the yellow color is removed from the tissue sections.
15. Rinse thoroughly in several changes of Distilled Water and remove slides.
Nuclear Staining
16. Place slides in the ‘Working Weigert’s Iron Hematoxylin Solution’ for 20 minutes. Agitate slides several times during the 20 minutes. Remove slides.
17. Wash well in running tap water until the water runs clean of excess hematoxylin.
18. Rinse thoroughly in several changes of Distilled Water and remove slides. Trichrome Staining
19. Place slides in the room temperature One-Step Trichrome Stain for 45 minutes. Remove slides.
20. Rinse slides thoroughly in several changes of 0.5% Acetic Acid. Agitate slides to remove excess Trichrome Stain. Total time should be approximately 3 minutes. Do not rinse in Distilled Water.
Dehydration
21. Transfer slides to the SAKURA DRS2000 Automated Stainer. Use programmed Staining Method, '95% start TRICHROME’.
22. 95% Alcohol, 45 seconds
23. 100% Alcohol, 1 minute
24. 100% Alcohol, 2 minutes
Clearing
25. Xylene, 3 minutes
26. Xylene, 4 minutes
27. Xylene, 5 minutes
28. Xylene, End Station
Coverslipping / Mounting
29. Remove the slides from the SAKURA stainer and place the staining rack in a green chemical resistant Tissue-Tek staining dish filled with Clear-Rite 3.
30. From Clear-Rite 3 coverslip using Permount and appropriate sized coverglass.
31. Label slides if necessary and arrange accordingly.
PREPARATION OF HAEMOLYMPH SMEAR
A grease free glass slide was labeled on one edge and marked with the sample name. Marking the slides makes it convenient to identify the surface of the slide that contains the smear. Take a live healthy specimen and cut the chelate leg carefully. Place two to three drops of haemolymph on one corner of the slide. Place another clean glass slide at an angle of 450 and pull the slide to another corner of the slide to make a thin smear. Presence of grease on the slide would prevent uniform distribution of the sample resulting in an uneven smear. Taking too much of the sample would result in excessively thick smear. Similarly, taking a very miniscule part of the sample make it very difficult to look for cells. The smear was air dried and heat fixed using a Bunsen flame at a comfortable height.
The smear must not be forcibly dried by applying heat. It is convenient to heat fix the smear by gently passing the slide through the Bunsen flame once or twice. Excessive heating of the slide must be strictly avoided. Fixed smears were placed on a staining rack over a sink or other suitable receptacle. Smears were stained easily separately with any of the stains like alkaline methylene blue for 1 to 15 minutes; with Carbolfuchin for 5 to 10 seconds; with Crystal violet for 20 to 30 seconds; with Safranine for 1 minute. Stained smears were washed gently in running tap water for a few seconds. Blot the slides dry with filter paper. Be careful not to rub the smear when drying the slide because this will remove the stained cells. Stained smears were air dried completely.
Add 1 to 2 mls of the DPX mount on the air dried slides containing the smears using a glass rod. Place the slides on a hot plate for a few minutes till the DPX mount begins to fume. As soon as mount begins to fume, remove the slides from the hot plate and place thick glass cover slips over the slides. Invert the slides so that the mount easily spreads over the slide. Gently press the cover slips with another slide. Do not press too much as it causes damage to the cover slips. Air dry the mount preparations and observe under 100X oil immersion objective.
DOCUMENTATION Using a Nikon E-400 fitted with a Spot Insight camera, six high-resolution color digital micrographs are taken for each of the three crabs per strain. (Three for the heart) The micrographs are taken following a strict protocol that insures that valid comparisons can be made across strains. After all the crabs are documented, half of them will have their images processed into smaller JPEG files and cataloged for posting on the website. This results in a representative survey of the morphology of three tissues from three treatment protocols as expressed within a strain.
RESULTS The circulatory system is the communicating organ system as it communicates with various systems of the body. It ensures proper distribution of oxygen and nutrients apart from the collection of metabolic wastes and delivering to the excretory organs like kidney. The circulatory body fluids transport various chemical substances necessary for metabolic continuity like hormones etc., the system of structures consisting of the heart, blood and blood vessels is named as circulatory system. In these animals the system of cavities should be considered as haemocoel and the blood which fulfils the characters of a circulatory fluid and these of inertial lymph should be caused haemolymph.
The pigment haemocyanin is found in the blood of most crustaceans, hence it is light blue in colour. The marine crab Carcinusmaenas, the estuarine crab Scylla serrata and the freshwater crab Parathelphusapantherina were selected for experimentation. The animals were collected and brought to the laboratory for acclimatization. The animals were dissected and heart of the animal has been subjected to the effects of some common drugs like Adrenaline, Atropine and Ephedrine. The observations indicate that the drugs like Adrenaline and Atropine stimulate the heart and hence increase in the heart beat whereas Ephedrine inhibited the heart beat or showed no action on the heart.
Similarly, the crabs were subjected to the effects of Ringer solution. It was observed that the toxic effect of the Ringer solution disturbs the regular working of heart and results in uncountable heart beats. The hearts of the three different crustaceans were isolated for the histopathology process to study, diagnose and to differentiate between the cardiac muscles of the crabs. It was observed that edema was seen in all the smears but it was higher in marine species than the estuarine and freshwater species. Vascular degeneration was observed in all the species but it was higher in estuarine crab than the other crabs. Inflammation was also seen but except marine species, the others show inflammation.
There were no toxic accumulation and pathogens observed. Haemolymph from all the three crustaceans were collected and made into smears. Unlike human blood, haemolymph of crustaceans is less denser and light blue in colour. This colour is due to the presence of the pigment named, haemocyanin. Since haemolymph is the circulatory fluid of the crabs, any drug that added to the heart easily communicates with the entire circulatory system and also with the nervous system. It was observed that the smears were even and contains many cells which are irregular in their shape and size. Some of the cells were stained pale blue in colour and some are darkly stained. Some cells were found in groups. There were some nucleated cells observed here and there among the other cells.
DISCUSSION
The available literature reveals that the heart rate in crustaceans influenced by a number of factors like body size, activity, respiration, stress, light, blood, moulting, diurnal cycle, PH etc. The heart beat frequency has been studied with a conclusion that alterations in heart rate occurs readily with change in environment and have an impact upon heart rate of marine and aquatic crabs. Depletion in the rate of oxygen consumption upon exposure to heavy metal stress weight be due to a penetration of the pollutants at sub-cellular levels and damage of gill tissue, thereby failure of an alternative compensatory mechanism to achieve energy generation for combating toxic stress. Present study was under taken to study the effect of chemicals such as Adrenaline, Atropine and Ephedrine on cardiac physiology of crabs Carcinusmaenas, Scylaserrata and Parathelphusapantherina.
The obtained results clearly indicates that the effects of chemicals i.e., Adrenaline, Atropine and Ephedrine initially inhibit the heart rate which indicates animal try to settle-down into the chemical medium but later on the effects of toxicants accelerate the metabolic activity of the animals which accelerate the rate of heart beat in a crab after this treatment. Then the heart rate slowly decreases as the animal dies. Haemolymph contains haemocyanin, which is oxygen binding site in blood. It is known, that the frequencies of crustaceans heart rate differ under different environmental conditions. It varies not only dismal rhythm, but also lie to temperature, hydrogen ion concentration, toxicants, sex and size. Hence recording time of observations and other factors were also taken into consideration and kept constant.
Thus any environmental factor that alters the process of oxygen uptake can be expected to affect circulation. Of course it is not exclude the possibility of some chemical acting directly on the heart and blood vessels. Crustaceans possess an open type of circulatory system and the haemolymph flows in the blood sinuses. A dorsally situated heart is present in most crustaceans. Though a true heart is lacking in Cirripedes and many Copepods and Ostracodes (Lockwood, 1968). The brachyuran heart is rhomboidal in shape and helps in circulating the haemolymph in the body with the help of its rhythmic beating (Lock Wood, 1968).
Crustaceans are the best studied invertebrate among which freshwater crabs have been intensively investigated with reference to their physiological aspects (Maynard, 1960; Vasantha and Gangotri, 1979). The data which available on the rate of heart beat in a variety of crustaceans list it is influenced by several factors of which size (Posser, 1973). As per the general rule it might be stated the heart rate varies inversely with body size and the trend is valid for most of the crustaceans. Blood volume has been determined in a number of crustaceans including crabs and it is evident that it is highly variable(Maloeuf, 1939; Schwarzkopf, 1955), studied different heart rates in a variety of crabs of different body weights and he showed clearly that the heart rate decreases in heart exponentially with increasing body size.
Environmental pollutants brings about the damage to different organs of disturb the physiological and biochemical processes of the organism following exposure to pollutant. Effects of different pesticides, inorganic ions, drugs and antibiotics on crustaceans hearts specially crabs have been used by many workers to reach the details about adrenergic and cholinergic property of crustacean heart (Agrawal et al., 1965; Bain, 1929; Davenport, 1941). Some important contributions have been made regarding cardio-vascular system by Cameron (1975) in land crab Gecarcinuslateralis. Likewise some other (Ashsanullah and Newell, 1971; Taylor et al., 1973; Hume and Belind, 1976) have been studied about cardiovascular system in Carcinusmaenas.
The hearts of various invertebrates studied differ greatly in their sensitiveness to the action of the drugs. The action of the alkaloids on the heart when introduced into the intact animal is therefore complicated by their action on the central ganglia or brain and on the peripheral ganglia other than those in the heart. The solutions of the alkaloids may be applied to the surface of the excised heart and empty heart or the heart may be filled with the solution. The acceleration of rhythm is followed by depression and if the concentration of the alkaloids is great, by complete cessation of the rhythm, the heart remaining excitable to direct stimulation. The point of action of the alkaloids in the heart is not yet known.
On the myogenic theory of heart beat their stimulating effects may be due to action on the accelerator nervous mechanism or to a direct action on the heart muscle. On the neurogenic theory the augmentation of the rate of the beats can hardly be accounted for except by direct action on the local ganglia, while the increased amplitude of the contractions may be due to the action on the muscle. To answer the question whether the alkaloids act on the nervous or on the muscular tissue in the heart or on both, several investigators have studied their action on the embryonic heart on the theory that the heart on the embryo begins to beat before any nervous elements are present. Pickering (1893, 1894- 95) found that Atropine and other alkaloids accelerate the embryonic heart, while strong solutions of Atropine depress the rhythm without any primary stimulation.
Cyrillo (1901) states that Atropine depresses the embryonic heart. This investigator finds, moreover, that the action of the principal alkaloids on the embryonic heart is the same as on the heart of adults, from which he concludes that these drugs act primarily on the heart muscle, their action on the nervous tissue in the heart being entirely of a second character. But Carlson proposed opposite conclusion that the primary action of the alkaloids is on the ganglion cells in the heart and not on the muscle. This conclusion is based on the results on the heart of Limulus. Cardiac muscle (heart muscle), like skeletal muscle, is also striated but involuntary muscle responsible for the pumping activity of the vertebrate heart. The individual muscle cells are joined through a junctional complex known as the intercalated disc and are not fused together into multinucleate structures as they are in skeletal muscle. Though unlike skeletal, cardiac muscle cells are short and branched with a single, centered nucleus.
They are also involuntary or not under immediate conscious control. Rather than Z-disks, which join skeletal muscle cells, intercalated disks join cardiac muscle fibers. Cardiac muscles are located only in the heart. Unlike skeletal, cardiac muscle can contract without extrinsic nerve or hormonal stimulation. It contracts via its own specialized conducting network within the heart, with nerve stimulation causing only an increase or decrease in rate of conducting discharge. The heart also has some very beneficial features such as an increased number and larger mitochondria, which allow it to produce more ATP. This is very important since the heart is constantly contracting and relaxing. Cardiac muscle can also convert lactic acid produced by skeletal muscle to ATP.
This is quite ingenious since lactic acid is a by-product of muscle when in a deoxygenated state, a state that would be detrimental to cardiac muscle. This muscle also remains contracted 10 to 15 times longer than skeletal muscle due to a prolonged delivery of calcium. Likewise, it also has a relatively long refractory period, lasting several tenths of a second, allowing heart to relax between beats. This also allows heart rate to increase significantly without causing it to go into tetanus, which would be fatal since it would cause blood flow to cease. Crustaceans possessing many primitive features tend to have myogenic hearts, although neurogenicity is dominant in the more advanced malacostracan groups and possibly members of the Ostracoda.
Exactly how the heart is regulated, via neuronal and neuro-hormonal controllers, has recently been investigated and there is a long history of examining the effect of environmental factors (e.g., hypoxia, salinity) on aspects of cardiac function (McMahon, 1999a, 2001; De Pirro et al., 1999). In particular the advent of non-invasive techniques to measure heart rate has opened up possibilities for more realistic measurements both in the laboratory and the field (e.g., Paul et al., 1997; Lundebye and Depledge, 1998; Bloxham et al., 1999).
CONCLUSION This report will be the basis for the future studies on different crustaceans and molluscans. In attempt to evaluate the effects of various drugs on different habitat crabs, we conclude that that the drugs like Adrenaline and Atropine stimulate the heart and hence increase in the heart beat whereas Ephedrine inhibited the heart beat or showed no action on the heart. Similarly, the crabs were subjected to the effects of Ringer solution. It was observed that the toxic effect of the Ringer solution disturbs the regular working of heart and results in uncountable heart beats and haemolymph of crustaceans is less dense.
ACKNOWLEDGMENT Research author was very gratefully thanks to my Research Supervisor Dr. J.M.V. Kalaiarasi and members from the School of Environmental Toxicology and Biotechnology, Department of Advanced Zoology and Biotechnology, Loyola College, Chennai for their cooperation for preceding the research works and for encouraging me to perform the research. Authors are grateful to IJCRR editorial board members and IJCRR team of re-viewers who have helped to bring quality to this manuscript.
Englishhttp://ijcrr.com/abstract.php?article_id=365http://ijcrr.com/article_html.php?did=3651. P. Tyagi, Cardiac pharmacology of the freshwater crab Paratelphusamasoniana, (Henderson) [Department of Zoology, D. A. V. College, Muzaffarnagar (U. P), India, Received January 20, 1970]. (Communicated by Dr. B. S. Chauhan, F. A. Sc.)
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Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareSYNTHESIS AND CHARACTERIZATION OF DIPHENYLTIN (IV) COMPLEXES WITH CYCLOPROPANE AND CYCLOPENTANE CARBOXYLIC ACIDS
English4650Tanzeel Ur RehmanEnglish Misbah ZahidEnglishAim: Compounds of diphenyltin carboxylates were prepared by using two different ligands i.e. cyclopropane and cyclopentane. Materials and Method: Solvent used for this purpose in CDCl3. The NMR spectra of 13C and 119Sn of CDCl3 solution of these compounds have been recorded. FTIR spectra are also recorded. CHNS analysis has been done to record the percentage of carbon and hydrogen in these compounds. Results: NMR and FTIR spectra are recorded and percentage of carbon and hydrogen was obtained by using elemental analysis. Conclusions: The values of the chemical shifts of the diphenyltin group give the proof that these compounds are monomeric species within the solutions no matter of their structure within the solid state.
EnglishDiphenyltin carboxylates, Cyclopropane, Cyclopentane, FTIR spectraINTRODUCTION
Organometallic compounds contain at least one C-Metal bond. Organometallic compounds are also known as metalorganics, metallo-organics and organo-inorganics. All Gillman and Grignard reagents are also examples of such organometallic compounds. Organometallic compounds contain also transition metals. Ferrocene and Tetracarbonyl nickel are examples of such organometallic compounds. Boron, silicon, arsenic, and selenium are also considered to form organometallic compounds along with other traditional metals and semimetals [1].
Organometallic compounds of Tin
Compounds containing tin with hydrocarbon substituents are called organotin compounds or stannanes. Organotin chemistry consists of wider field of organometallic chemistry. Diethyltindiiodide was the first organotin compound, discovered by Edward Frankland in 1849 [2]. Organotin compounds are classified as R4 Sn, R3 SnX, R2 SnX2 and RSnX3 .
In compounds of industrial importance, R is usually a butyl, octyl-, or phenyl group and X, a chloride, fluoride, oxide, hydroxide, carboxylate, or thiloate. Organotin compounds have one or more carbon-tin covalent bonds that are responsible for the specific properties of these molecules. Essentially all organometallic tin compounds are of the Sn (IV) type. The only well established compound with tin having the oxidation state +2 is the tin (II) cyclopentadienyl (C10H10Sn). There are four classes of organotin compounds depending on the number of alkyl group. These series are designated as mono-, di-, tri-, and tetraorganotin compounds [3].
Uses and applications of organotin compounds
1. Organotin compounds can be powerful bactericides and fungicides depending on the organic groups. [4] 2. Tributyltins are utilized as industrial biocides, for example, as antifungal agents in breweries, industrial cooling systems. These are used in textiles and paper, paper mill systems and wood pulp. These are also used in marine anti-fouling paint [5, 6].
3. Organotin compounds are widely studied class of meta-based antitumor drugs [7].
4. Triphenyltins are applied as active components of agricultural fungicides and antifungal paints [8].
5. Organotin compounds are used in the treatment of hyperbilirubinaemia [9].
6. Organotin compounds are used for wood preservation [10].
7. Addition of Organotin compounds to PVC increases its stability [11, 12].
8. Organo metallic transition complexes also have a role in molecular rearrangement processes [13].
Organotin carboxylates
As for organotin carboxylates are concerned, Sn exists in two oxidation states Sn(II) and Sn(IV) in these compounds. Sn(II) formate and acetate are made by simple methods. Tin acetate in the oxidation state of two is stable and can be stored for some months, but over longer periods of time it undergoes slow oxidation. It hydrolyses slowly over several hours in water, but the adduct (CH3 COO)2 Sn. CH3 COOH is formed by dissolving Sn(II) acetate in glacial acetic acid. This adduct is unhydrolysed, even in boiling water. In addition to these simple ones, evidence has been presented for many more carboxylate species of Sn((II). Thus CH3 COOSn, (CH3 COO)2 Sn, (CH3 COO)7 Sn, (CH3 COO)5 Sn and (CH3 COO)3 Sn have been reported. The tri-acetatostanates have been well characterized. The organotin (IV) carboxylates are of particular interest in a way that they appear to exist in more than one form [14].
For example when triphenyltin chloride reacts with, for example, formic acid and acetic acids, the products [(Ph)3 SnOOCH and (Ph)3 SnOOCH3 ] are very insoluble. These insoluble products are believed to be associated by bridging carboxylate groups, either as ring or linear polymers [15]. If however, the polymeric forms of these are heated in cyclohexane at 100° C for several hours, they are both converted to new soluble forms. A remarkable point of interest is that the soluble and insoluble forms of these organotin carboxylates are sublimable at high vacuum with out Interco version [16]. IR is one of the most important spectroscopic methods used for qualitative and quantitative analysis.
It is based on the fact that each compound has its own unique spectra and certain functional groups absorbent about the same wavelength even in different molecules. Its single most important use has been made for the identification of organic compounds whose spectra are generally complex and provide numerous maxima and minima that are used for comparison purposes. Indeed in most instances, the IR spectrum of the compounds especially of organic compounds provides a unique finger print, which is readily distinguished from the absorption pattern from all other compounds because only optical isomers absorb in the same way.
Absorption of IR radiation is confined largely to molecular species for which small energy differences exist between various vibration and rotational states. NMR is an important technique used for the analysis of compounds. Like electron, nucleons also have spin .If an atom has an even number of nucleons, the spins cancel out and there is no overall magnetic moment [17]. If however, an atom has an odd number of nucleons, there is an overall magnetic moment. As a result, the nucleus can take up one of the two orientations whose energy splits in the presence of an external magnetic field, this splitting of the energy form the basis of nuclear magnetic resonance and NMR spectroscopy. Elemental analysis is an experimental work to determine the amount of an element in a compound in weight percent.
Different experiments are used to determine elemental composition as there are many different elements. CHN (carbon, hydrogen, and nitrogen) is the most common type of elemental analysis. CHN analysis is especially useful for organic compounds. The elemental analysis of a compound is used for the determination of the empirical formula of the compound. The formula which shows the simplest whole number ratio of the elements in a compound is called empirical formula. Each CHN analysis should include at least 5 mg of transferable sample. CHN analysis provides a quick and inexpensive method to check sample purity, and in conjunction with mass spectrometry and NMR data, can be used to characterize a compound.
EXPERIMENTAL
Chemicals used Dry Toluene, Diphenyltin (IV) oxide were purchased from Riedal-de Hean and used with out further purification. Instrumentation IR (FTIR, 3000MX, Bio-Rad Excalibur Series, USA), 1 H AND 13C NMR (Advance 300 MHZ NMR, Bruker). Procedure A (0.5 ml, 2mmol) of cyclopropane carboxylic acid was dissolved in dry toluene in round bottom flask two-necked flask. To this solution, Ph2 SnO (0.91, 1mmol) added with constant stirring. The solution was refluxed for four hours. Water produced as a by product was removed through Dean Stack apparatus. Solvent was evaporated by rotary evaporator under reduced pressure. Solid obtained was dried in air.
ELEMENTAL ANALYSIS As for as compound 1 is concerned, the calculated amounts of carbon and hydrogen are 54.21% and 4.52% respectively and found amounts are 46.56% and 4.63% respectively. In case of compound 2, the calculated amounts of carbon and hydrogen are 54.21% and 4.52% respectively and found amounts are 46.56% and 4.63% respectively.
DISCUSSION
IR spectroscopy
As for as spectrum is concerned we see a prominent peak at 450cm-1in Table-2, which indicates the formation of metal to oxygen bond. Another change that we observe in this spectra as compared to ligand spectra is stretching vibration of C=O, which normally occurs at 1700cm-1 but these are shifted to lower wavelength side because when metal oxygen bond forms, most of the electron density is shifted to metal and as a result the bond is strengthen and vibration occurs at lower wavelength side. This bond formation is also evidenced by the fact, in this spectrum, the peak also appears as consequences of the M-O bond formation. Another important thing that we determine from this spectrum is the coordination number of the central atom. For this we calculated the value of the V which is determined by measuring the difference between the symmetric and asymmetric vibrations.
As shown in the above table, peaks are observed at 555 cm-1, 515 cm-1 and 477 cm-1, 419 cm-1 for Sn-C and Sn-O bonds for compounds 1 and 2 respectively. Another thing observed the value for ?v which to be 102 cm-1 and 126 cm-1, these values indicate that the ligands act as a monodentate ligand. Similarly another peak which appears at 3300-2500 cm-1for O-H is disappeared in case of the spectrum of the complex due to the dissociation of this proton. The formation Sn-O bond is also evident by the fact that a peak is observed for C-O. This peak is appeared because after bond formation most of the electron density is shifted to Sn as a result C=O changes to C-O.
It is evidence from the table-3, in the first complex peak for proton 1, 2, 3, 4 and 5 are at 6.896 ppm, 7.148 ppm, 7.282 ppm, 1.834 ppm and 0.904 ppm. The spectrum is complex due to carboxylato and alkyl groups attached to the metal which are very bulky. In the case of second compound it is evidence from the table that in the first complex, peaks for proton 1, 2, 3, 4 and 5 are at 6.896 ppm, 7.148 ppm, 7.282 ppm, 1.834 ppm and 0.904 ppm.
It is evidence from the table-4 that in the first complex peaks for carbon 1, 2, 3, 4, 6, 7 and 8 are at 137.5 ppm, 128.8 ppm, 130.5 ppm, 185.65 ppm, 17.0 ppm, 71.0 ppm, and 11.0 ppm respectively. For the second complex, peaks for carbon 1, 2, 3, 4, 6, 7, 8 and 9 are at 128.71 ppm, 134.62 ppm, 135.81 ppm, 135.65 ppm, 185.5 ppm, 144.18 ppm, 77.25 ppm and 25.85 ppm respectively. The spectrum is complex due to carboxylato and alkyl groups attached to the metal are very bulky. As for as very bulky groups are attached to metal, so from 13C NMR and proton NMR spectra we could not easily identified the metal to ligand bond and complex formation.
Elemental Analysis The difference in amounts for compound 1 may be due to impurities or instrumental error. For compound 2, amounts are almost equal.
CONCLUSION These compounds are monomeric species within the solutions no matter of their structure within the solid state.
ACKNOWLEDGEMENT Authors are thankful to Professor Dr. Saqib Ali, Head of Department Quaid-I-Azam University, Islamabad, Pakistan whose advice made energized to do this work. Authors acknowledge the huge help received from the technical staff of the QAU laboratory for NMR analyses. Authors accede the immense advice accustomed from the scholar community whose online writing are cited and included in references of this manuscript. The authors appreciate authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.
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Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524181EnglishN-0001November30HealthcareCOMPARISION OF THE ADVERSE EFFECTS PROFILE OF TRAVOPROST VS BRIMONIDINE/TIMOLOL IN PATIENTS OF PRIMARY OPEN ANGLE GLAUCOMA IN CENTRAL IDIAN POPULATION OF BHOPAL
English5154Rekha MehaniEnglish Major V. K. YadavEnglish Rajnish Kumar SankadiaEnglish Sarang GhodkiEnglish Tanu GargEnglishAim: To compare the adverse effects profile of Travoprost vs Brimonidine/Timolol in patients of Primary Open Angle Glaucoma(POAG) Methodology: In this randomized open label 12-week study, 70 patients were randomized to receive either 0.004% of Travoprost once daily in the evening or Brimonidine/Timolol combination twice daily. Their safety was concluded by monitoring their adverse effects during follow-up visits at 2, 4, 8, and 12 weeks. Results: Both treatment regimens were well tolerated during the period of study. Patients in the Travoprost group had a higher incidence of ocular irritation (30%), pigmentation of skin (33%), Thickening of eyelashes (39%) and hyperemia (36%) when compared to the Brimonidine/Timolol group which showed only ocular irritation (21%) and foreign body sensations (28%). Conclusions: The incidence of adverse effects were not significantly different between Travoprost and Brimonidine/Timolol therapy. Both had favourable safety profiles. However, Travoprost had more local side effects profile when compared to Brimonidine/Timolol.
EnglishBeta blocker, Intraocular pressure, Prostaglandin analogue, ?2 agonist, Adverse effectsINTRODUCTION
Glaucoma is an optic neuropathy characterized by acquired loss of retinal ganglion cells and atrophy of the optic nerve leading to vision loss. Glaucoma is the second leading cause of blindness globally, (Quigley HA. 1996) accounts for 12.3% of total blindness (Congdon N et al). Elevated intraocular pressure (IOP) is a primary risk factor both for the development of glaucoma and for progression of optic nerve changes and visual field loss in the disease (Morrison JC. 2005). Primary open-angle glaucoma (POAG), the most common type of glaucoma is characterized by chronically elevated IOP with no known cause for the elevated IOP or optic neuropathy.
The aim of treatment in glaucoma is to reduce IOP. Recent randomized, controlled clinical trials have shown that lowering IOP is effective in delaying or preventing the development of glaucoma in patients with ocular hypertension (OHT) and in delaying or halting the progression of established glaucoma.(Haijl et al 2002, Kass MA et al 2002). Further IOP reduction is beneficial in reducing the risk of progression of vision loss even when IOP is already within the normal range (Collaborative Normal-Tension Glaucoma Study Group 1998). Evidence suggests that very low IOP provides the best visual outcomes for patients.
(The AGIS Investigators 2000; Lichter et al 2001). Analysis of data from the Early Manifest Glaucoma Trial showed a 10% reduction in the risk of progression associated with each 1 mmHg of IOP reduction (Leske et al 2003). Medical treatment is the first line of management and includes the use of several classes of topical agents. Brimonidine /Timolol is the commonly used drug combination to reduce IOP. Travoprost, a prostaglandin analogue has come up with powerful ocular hypotensive effects (DuBiner HB, Laurence L Bruton)9,10 The objective of present study was to compare the safety profile of Travoprost with Brimonidine / Timolol in patients with POAG.
METHOD All the cases studied were attending the outpatient Department of Ophthalmology at Peoples Medical College Bhanpur Bhopal. Study duration was 18 months. While selecting the cases for the study special care was taken to include only newly diagnosed cases of POAG. Necessary approval were taken (CTRI/2011/11/002105). Informed consent from the patient was obtained after explaining to them the details of the study. Inclusion criteria are patients with Primary open angle glaucoma aged more than 40years with IOP more than 21mmHg having visual acuity 6/24 or better.
Patients with inflammation, ocular infection, advanced cataract and patients of bronchial asthma and cardiac disease were not included in the study. Patients were divided into two groups Group A and B based on simple random sampling. One group was treated with 0.004% of Travoprost eye drops once a day in the morning and the other with fixed combination of Brimonidine/Timolol eye drops twice a day. The intraocular pressure was measured at baseline, 2, 4, 8, and 12 weeks of the visit using Applanation tonometer and side effects were recorded. Total 5 patients did not come for the follow up and study was completed in 65 patients (Group A n = 33,Group B n = 32 ).
RESULTS Both treatment regimens were well tolerated during the study. Patients in the Travoprost group had a higher incidence of ocular irritation (30%), pigmentation of skin (33%), Thickening of eyelashes (39%) and hyperemia (36%) when compared to the Brimonidine/Timolol group which showed only ocular irritation (21%) and foreign body sensations (28%). There were no serious side- effects observed in this study. Both the drugs were well tolerated.
Travoprost had a higher incidence of adverse effects. ocular irritation (30%), pigmentation of eyelashes (36%), Change of iris colour (25%), Thickening of eyelashes (39%)and hyperpigmentation (33%) when compared to the Brimonidine/Timolol group which showed only ocular irritation (21%). There was no ocular pain with Brimonidine/Timolol, in contrast to the Travoprost group where 10% of the patients suf fered from ocular pain. Conjunctival hyperemia (36%) with Travoprost. From our observations Travoprost appears to have more adverse effects.
DISCUSSION Travoprost acid, the biologically active form of Travoprost, is a prostaglandin F2α analog and a fully selective agonist to the prostaglandin F receptor (Laurence L Bruton Franks WA, Sharif NA 2003, Sharif NA 2003, Hellberg MR et al). It reduces IOP by increasing the outflow of aqueous humor through the uveoscleral pathway (Schachtschabel U et al 2000, Denis P et al 2007). In studies to evaluate the relative incidence of hyperemia between prostaglandins, Netland et al found that the incidence of hyperemia caused by latanoprost was 27.6%, while Travoprost had a rate of 49.5%, and Cantor et al observed hyperemia in 21.1% of eyes treated with bimatoprost and in 14.8% in eyes treated with Travoprost (Netland et al, Cantor LB et al 2006).The use of Travoprost 0.004% induced a conjunctival hyperemia incidence of 32.5%–49.5%, whereas timolol maleate 0.5% treatment had an incidence of 7%–14%(Denis P et al 2007 , Goldberg I et al 2001).In our study we found hyperemia in 36% of patients which is comparable to other studies. Hyperemia was usually mild and unlikely to interrupt clinical studies. In fact, improvement of hyperemia during continued dosing has been reported (Goldberg I et al 2001).
Prostaglandin analogues (PGA) can also induce darkening of the iris, and its incidence in the literature varies according to the different methods used in its evaluation. Netland et al also reported that iris hyperpigmentation was observed in 5.2% of eyes treated with latanoprost and in 3.1% in eyes treated with Travoprost and in our study it was more that is 33%. It is much more higher as compared to other studies. The eyelashes can suffer some changes during treatment with Travoprost and other PGAs. These drugs can induce eyelashes to increase in number and can cause alteration in their length, thickness, and darkness. In our study we found thickening of eyelashes in 39% of patients. Other body systems are not considerably affected by Travoprost treatment (Denis P et al 2007 ).
Brimonidine is a selective α-2 adrenergic receptor agonist. Brimonidine has a dual mechanism of IOP lowering: it both reduces aqueous humor production and stimulates aqueous humor outflow through the uveoscleral pathway (Toris CB et al). Brimonidine has a favourable safety and tolerability profile. Unlike the β-adrenergic antagonists, there are no cardiopul- monary contraindications to its use, and Brimonidine can be safely and effectively used by patients on systemic antihypertensive beta-blocker therapy (Schuman JS. 2000). In contrast to the prostaglandin analogues, Brimonidine has not been associated with eyelash growth or increased pigmentation of the iris or eyelids.
The side- effects associated with Brimonidine treatment are usually ocular burning, foreign body sensation, allergic conjunctivitis, and ocular pruritus. The most common systemic side-effects are oral dryness and fatigue or drowsiness. Brimonidine/Timolol fixed combination also proved better in terms of number of adverse events as observed in both groups, with 20% more adverse events seen in the Travoprost group (Table 1). Brimonidine/ Timolol fixed combination has more foreign body sensation than Travoprost group. There were no serious, unexpected, related adverse events reported for any therapy.
Timolol reduces intraocular pressure (IOP) by suppression of aqueous secretion and prevents damage to optic nerve and subsequent loss of vision.10 Side effects are stinging, redness and dryness of eye, corneal hypoesthesia, blurred vision and allergic blephero-conjunctivitis. Ocular pain was almost similar in both groups. From our observations Travoprost appears to have more adverse effects.
CONCLUSION Travoprost and Brimonidine/Timolol are proven drugs for the treatment of Primary open angle glaucoma. The choice of drug will depend on many factors including the adverse effect profile. Present study demonstrated a favourable safety profile for the Brimonidine/Timolol combination which produced fewer local adverse effects. however Brimonidine/ Timolol combination has to be avoided in the patients of bronchial asthma for the fear of precipitation of asthma attack.
ACKNOWLEDGEMENT Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.
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