Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-5241103EnglishN2018February1HealthcarePrevalence and Factors Influencing Depression in Patients with Stroke Attending a Tertiary Care Teaching
Hospital, a Cross Sectional Study
English0106Shaik Afsar PashaEnglish Pavan Kumar TVEnglish Chaitanya CHEnglishBackground: Stroke is a major public health problem contributing to significant morbidity and mortality across the globe. In spite of many reviews documenting a strong association between stroke and depression, it is the most ignored aspect in many developing countries including India, due to paucity of studies on the subject. Hence the current study was conducted with an objective of assessing the prevalence of depression among the stroke patients and factors influencing it in a tertiary care teaching hospital
Materials & Methods: This cross sectional study was conducted in the department of Neurology and the department of Psychiatry in NRI General Hospital. The study had included 56 eligible stroke patients and evaluated them for depression using DSM-IV TR Diagnostic criteria and Hamilton Depression Rating Scale (HAM-D).
Results: The prevalence of depression in study population was 46.4%, out of which 21.4% had minor depression and 25% had major depression. The demographic factors which have shown increased risk of depression were female gender, primary school educational status, middle socioeconomic class and living in an extended nuclear family or joint family. But none of the associations had shown statistical significance. The disease related factors associated with increased risk of stroke were presence of aphasia, severe limitation of and presence of stressful life event. Out of these only severe limitation of ADL has shown statistically significant association.
Conclusions: The prevalence of depression is very high in patients affected by stroke. The major factors which were associated with increased risk of depression were female gender, presence of aphasia, severe limitation of ADL and presence of stressful life events.
EnglishDepression, Stroke, Aphasia, Stressful life eventsStroke is a major public health problem accounting for 5.5 million deaths worldwide annually, with 44 million disability- adjusted life-years lost.1 A systematic review of 56 population based studies found a 42% decrease in stroke incidence in high income countries while in low income countries, the stroke incidence more than doubled in recent years.2 Stroke is one of the leading causes of death and disability in India. Currently, the stroke incidence in India is much higher than Western industrialized countries. The reported age adjusted
prevalence rate of stroke ranges from, 84 to 262 per 100,000 among rural population. It ranges from 334 to 424 per 100,000 among urban population. The incidence rate is 119-145/100,000 based on the recent population based studies”. 3-5 In India, the overall morbidity as assessed by DALYs was 795.57 per 100,000 person-years.6
Considering the devastating consequences of stroke at personal and family level, it is likely that stroke may have serious negative impact on psychological health of the affected person. Depression is reported to be one of the common sequelae of stroke. Recent systematic reviews have reported a pooled estimate of depression in stroke patients to be about 33%.7Though it was presumed that left hemisphere strokes increase the risk for post-stroke depression (PSD), a recent systematic reviews did not support the hypothesis.8,9The depression in stroke patients is reported to be the strong predictor of adherence to treatment, quality of life of the affected patients.10 Hence, many of the recent studies have emphasized the importance of focusing on the psychological aspects apart from (neuro) biological factors, to achieve better
treatment outcomes and quality of life in stroke affected patients.11,12
In India, post-stroke depression is an ignored or highly under- diagnosed condition, hence poorly addressed. Studies documenting the burden and factors influencing depression can draw the attention of all relevant stakeholders including patients, their family members, health care providers at different levels. Hence there is a strong need for studies on the subject.
Objectives:
1. To assess the prevalence of depression among the stroke patients presenting to a tertiary care teaching
hospital in south India
2. To analyse factors associated with depression in the study population
MATERIALS AND METHODS
Study site: This study was conducted in the department of Neurology and the department of Psychiatry in NRI General Hospital, which is a tertiary care teaching hospital located in the state of Andhra Pradesh, South India.
Study population: The study population included all the adult patients diagnosed with ischemic stroke by clinical examination and confirmed by appropriate imaging (CT scan/ MRI Brain) and were attending follow up visits in neurology OPD 3 to 12 months after stroke
Sample size and sampling method: A group of 56 eligible and consenting participants were included in the study sequentially by convenient sampling.
Data collection tools:
DSM-IV TR Diagnostic criteria was followed to screen for Depression. Hamilton Depression Rating Scale (HAM-D) was used to assess the severity of depression in the study group. Lawton scale of Instrumental Activities of Daily Living (IADL) was applied to assess the degree of physical impairment. Mini Mental Status Examination (MMSE) was applied to assess cognitive impairment. Presumptive Stressful Life Event Scale (PSLES) was administered to find the role of stressful life events in post stroke depression.
Inclusion Criteria:
1. All adult patients with the diagnosis of Ischemic stroke made by a neurologist both clinically and with
CT/ MRI scan belonging to both genders
2. Conscious and cooperative and accompanied by at least one informant.
3. The stroke should be of first episode.
Exclusion Criteria:
1. Patients with past history of psychiatric illness.
2. Patients with neuro radiological evidence of hemorrhage.
3. Patients with duration of less than 3 months and more than 12 months from the stroke episode.
4. Patients who could not communicate or severely aphasic.
Study procedure: After obtaining informed consent, special proforma was prepared for collecting the socio-demographic profile. This consisted of socio demo graphic data, history of present illness, history of past medical and psychiatric illness and detailed neurological examination, CT scan and other important investigations. Patients meeting the criteria for depressive disorder due to general medical condition based on
DSM-IV TR criteria were administered the following tools. This study had cleared the institutional ethical committee requirements.
Statistical Methods
IBM SPSS statistical software version 21 was used for statistical analysis. Socio demographic variables like age and gender, religion, education, occupation, socioeconomic status, type of family etc. were taken as explanatory parameters. Presence of depression as assessed by HAM depression score was considered as primary outcome. Descriptive analysis of all the explanatory and outcome parameters was done. All the categorical variables were presented in frequencies and percentages. The numerical variables presented
in means and standard deviations. The association between various explanatory variables and depression was assessed by univariate binary logistic regression in the first step. Unadjusted odds ratios along with 95% CI were presented. Variables showing statistically significant association in univariate analysis were included in the multivariate binary logistic regression analysis, to identify the independent predictors of depression. IBM SPSS statistical software version 21 was used for statistical analysis.13
RESULTS
A total of 56 stroke patients, who satisfied inclusion criteria were included in the study. Following Table 1 illustrates the distribution of sociodemographic parameters in the study population.
Out of total 56 participants, 38 (67.9%) were males. Hindus constituted 80.4% of participants and the proportion of Christians and Muslims was 14.3% and 5.4% respectively. Majority (71.4%) were illiterates and 21.4% completed primary education and only 5.2% completed secondary education and higher. Four (7.1%) belonged to high socio economic status. The proportion of low and middle socio economic status people was 41.1% and 51.8% respectively. Forty six (82.1%) of them belonged to nuclear family, 6 (10.7%) belonged to extended nuclear family and 4 (7.1%) belonged to joint family.
The lesion was on left side for 32 (57.1%) patients and was on right side for remaining 24 (42.9%) patients. UMN facial palsy was seen in 19 (33.9%) of patients and aphasia was seen in 20 (35.7%) of patients. The most common lesion in CT was fronto parietal infarct, which was seen in 19(33.9%) patients, followed by capsuloganglionic infarct, seen in 15 (26.8%) of patients. (Table 2) As per Lawton instrumental activities of daily living, 19 (33.9%) people were having normal scores, 19 (33.9%) had mild limitation, 8 (14.3%) had moderate limitation and 10(17.9%) had severe limitation of activities of daily living. (table 2)
The prevalence of depression in study population was 46.4%, as 26 subjects out of 56 had depression of various severities. Out of the 26, 12 (21.4%) had minor depression and 14 (25%) had major depression. (table 3)
The demographic factors which have shown increased risk of depression were female gender (Odds ratio=2.410, 95% C.I. 0.763 to 7.605, P value 0.134), primary school educational status (OR=3.316, 95% CI 0.317 to 34.654, p value 0.317), middle socio-economic class. (OR=3.90, 95% CI 0.351 to 43.364, p value 0.268) and living in an extended nuclear family (OR=2.750 95% CI 0.266 to 28.433) or joint family (OR=3.0, 95% CI 0.266 to 28.433). But none of the associations had shown statistical significance. The disease related factors associated with increased risk of stroke were presence of aphasia (OR=1.711, 95% CI 0.568 to 5.152, p value=0.340), Severe limitation of ADL (OR=12.375, 95% CI 1.294 to 118.331, P value 0.029) and presence of stressful life event (OR=.667, 95% CI 0.509 to 5.461, P value 0.399). Out of these only severe limitation of ADL has shown statistically significant association.
DISCUSSION
Assessment of the epidemiology of stroke is a difficult but exciting challenge that is justified by the objectives of identifying vascular risk factors, establishment of needs for the implementation of dedicated services, and guiding and assessment of future preventive and therapeutic priorities.
As per a conservative estimate, one third of all people experience significant depressive symptoms at some time after the onset of stroke. Unfortunately, the potential of under-reporting or under-recognition of abnormal mood is common due to the inherent difficulties in assessing the mood changes among patients with neurological disabilities like dysphasia and/or dementia.7 Traditionally it has been considered that the greatest risk of depression is during the first few months of stroke onset. Conversely, Hackett et al., observed a consistency in the overall frequency of depression in their systematic review.7
In our study there were 67.9 % Male patients. Comparatively the proporion of males was 53.2% in the study by Aben et al.,14 and 55.4% in that of Carod Artal et al.,10.A 10 year follow-up study reported that though, strokes were marginally more common in males, it could be explained by confounding and that more research is needed to understand the gender disparity in stroke pathophysiology.15
Majority (71.4%) were illiterates and 21.4% completed primary education and only 5.2% completed secondary education and higher. Laborers (48.2%) and house wives (19.6%) were the most prevalent occupations, in the study group. Out of 56 participants, only 4 (7.1%) belonged to high socio economic status. The proportion of low and middle socio economic status people was 41.1% and 51.8% respectively. Forty six (82.1%) of them belonged to nuclear family, 6 (10.7%) belonged to extended nuclear family and 4 (7.1%) belonged
to joint family.
We found aphasia in 20 (35.7%) of our patients. Engelter et al.,16reported aphasia in 30% of ischemic stroke patients in a geographical defined population of 188,015. They concluded that individuals of advancing age and cardioembolism had higher risk for aphasia. Evidence also suggests that aphasia in stroke patients is associated with higher mortality 17, decreased rates of functional recovery 18,19, and reduced chances to return to work20compared with non-aphasic stroke patients .
The study found stroke lesions were more commonly on left hemisphere (57.1%) than right (42.9%). Similar findings (left:43% and right (37%) were found in the cohort study by Reid et al.,.15However, Cardo-Artal et al.,10 reported an equal prepondarence, while Aben et al., found higher involvment of right hemisphere (53.2%). As per Lawton instrumental activities of daily living, 14.3% had moderate limitation and 17.9% had severe limitation of activities of daily living. Evidence suggests that stroke survivors experience physical deconditioning and lead sedentary lifestyles and hence need to do exercise training (both aerobic and strength training).21Exercise training improves functional capacity, the capacity to perform activities of daily living and quality of life. It also reduces the risk for subsequent cardiovascular events. Hence physical activity goals and exercise prescription for stroke survivors need to be customized for the individual to maximize long-term adherence.21
In the current study, the prevalence of depression was 46.4%, with 21.4% cases of Minor depression and 25% Major depression. Carod-Artal et al,10found 38% of their patients belonging to depressed range, while Astrom et al.,22 reported 25% at acute stage and 31% after three months. A three year longitudinal study revealed that left anterior brain lesion, dysphasia and living were the important predictors of immediate
major depression.22
The demographic factors which have shown increased risk of depression were female gender (Odds ratio=2.410, 95% C.I. 0.763 to 7.605, P value 0.134), primary school educational status (OR=3.316, 95% CI 0.317 to 34.654, p value 0.317), middle socioeconomic class. (OR=3.90 ,95% CI 0.351 to 43.364, p value 0.268) and living in an extended nuclear family (OR=2.750 95% CI 0.266 to 28.433) or joint family (OR=3.0, 95% CI 0.266 to 28.433). But none of the associations had shown statistical significance. Females had higher proportion of depression compared to Males. Reid et al,15 highlight the rising proportion of elderly women hospitalized because of stroke. After adjusting for confounding variables, the authors found that women were more likely to have depression.
The disease related factors associated with increased risk of stroke were presence of aphasia (OR=1.711, 95% CI 0.568 to 5.152, p value=0.340), Severe limitation of ADL (OR=12.375 ,95% CI 1.294 to 118.331, P value 0.029) and presence of stressful life event (OR=.667, 95% CI 0.509 to 5.461, P value 0.399). Out of these, only severe limitation of ADL had shown statistically significant association. Many studies have reported major factors influencing depression on long term to be inability to work due to disability, dependence in activities of daily living, diminished social activity, being a housewife7, 10, 23 and cerebral atrophy.22 Usually by one year, patients with early depression recover, but those not recovered had a higher risk of developing chronic depression. 7, 24, 25 There were statistically significant differences in the proportion of people with mild and severe depression in patients with different levels of activity in Lawton instrumental scale of daily living. Even though the proportion of Major depression was higher in people with more limitation of activity, there was no clear increasing or decreasing trend observed with increasing levels of activity limitation.
On the whole, depression after stroke is influenced my multifactorial interaction of biological, psychological and social aspects and their understanding would facilitate targeted preventive strategies and more effective and comprehensive preventive programs.22, 26, 27
CONCLUSIONS
The prevalence of depression is very high in patients affected by stroke. The major factors which were associated with increased risk of depression were female gender, presence of aphasia, severe limitation of ADL and presence of stressful life event.
RECOMMENDATIONS
1. Adequate attention has to be given to depression and other psychological consequences of stroke while
managing patients with stroke.
2. There is strong need for large scale prospective studies and intervention studies to assess log term impact of depression on these patients and to provide guidance to clinicians on appropriate management.
LIMITATIONS
1. Lack of statistical significance of many of the association could be attributed to smaller sample size. This
also did not permit multivariate analysis to assess the confounding and interaction between the factors evaluated.
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.
Source of support – None.
Conflict of interest –Nil.
Englishhttp://ijcrr.com/abstract.php?article_id=2428http://ijcrr.com/article_html.php?did=24281. Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh S, et al. Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol. 2016;15:913- 24.
2. Feigin VL LC, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–69.
3. Pandian JD, Sudhan P. Stroke epidemiology and stroke care services in India. Journal of stroke. 2013;15:128-34.
4. Pandian JD SV, Read SJ, Thrift AG. Poverty and stroke in India. A time to act. Stroke. 2007;38:3063–9.
5. Prasad K VD, Meenakshi. Cerebrovascular disease in South Asia - Part I: A burning problem. JRSM Cardiovasc Dis. 2012;1:20.
6. Banerjee TK DS, Ray BK, Ghosal M, Hazra A, Chaudhuri A, et al. Disease burden of stroke in Kolkata, India: Derivation of disability-adjusted life years by a direct method. Neuroepidemiology. 2013;41:88–93.
7. Hackett ML, Yapa C, Parag V, Anderson CS. Frequency of depression after stroke: a systematic review of observational studies. Stroke. 2005;36:1330-40.
8. Carson AJ MS, Allen K, Lawrie SM, Dennis M, House A, Sharpe M. Depression after stroke and lesion location: a systematic review. Lancet. 2000;356:122–6.
9. Singh A HN, Black SE. The importance of lesion location in post stroke depression: a critical review. Can J Psychiatry. 1998;43:921–7.
10. Carod-Artal EJ, González JL, de Seijas EV. Quality of Life Among Stroke Survivors Evaluated 1 Year After Stroke. Stroke. 2000;31:2995-3000.
11. Kumar S. Sobering news about post-stroke depression. The lancet Psychiatry. 2017;4:2-3.
12. Hesdorffer DC. Comorbidity between neurological illness and psychiatric disorders. CNS spectrums. 2016;21:230-8.
13. Spss I. IBM SPSS statistics version 21. Boston, Mass: International Business Machines Corp. 2012:126.
14. Aben I DJ, Louseberg R, Vershey F, Wojciechowski F, Honig A, MRCPsych. Personality and Vulnerability to Depression in Stroke Patients. A 1-Year Prospective Follow-Up Study. Stroke. 2002;33:2391-5.
15. Reid JM, Dai D, Gubitz GJ, Kapral MK, Christian C, Phillips SJ. Gender differences in stroke examined in a 10-year cohort of patients admitted to a Canadian teaching hospital. Stroke. 2008;39:1090-5.
16. Engelter ST, Gostynski M, Papa S, Frei M, Born C, Ajdacic- Gross V, et al. Epidemiology of aphasia attributable to first ischemic stroke: incidence, severity, fluency, etiology, and thrombolysis. Stroke. 2006;37:1379-84.
17. Laska AC HA, Murray V, Kahan T, Von Arbin M Aphasia in acute stroke and relation to outcome J Intern Med. 2001;249:413–22.
18. Tilling K SJ, Rudd AG. . A new method for predicting recovery after stroke. Stroke. 2001;32:2867–73.
19. Paolucci S AG, Pratesi L, Traballesi M, Lubich S, Grasso MG. Functional outcome in stroke inpatient rehabilitation: predicting no, low and high response patients. Cerebrovascular diseases (Basel, Switzerland). 1998;8:228–34.
20. Black-Schaffer RM OJ. Return to work after stroke: development of a predictive model. Arch Phys Med Rehabil. 1990;71:285–90.
21. Billinger SA, Arena R, Bernhardt J, Eng JJ, Franklin BA, Johnson CM, et al. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2532-53.
22. Astrom M AR, Asplund K. Major Depressionin StrokePatients. A 3-Year Longitudinal Study. Stroke. 1993;24:976-82.
23. Gabaldon L, Fuentes B, Frank-Garcia A, Diez-Tejedor E. Poststroke depression: importance of its detection and treatment. Cerebrovascular diseases (Basel, Switzerland). 2007;24 Suppl 1:181-8.
24. Gaete JM, Bogousslavsky J. Post-stroke depression. Expert review of neurotherapeutics. 2008;8:75-92.
25. Gainotti G, Antonucci G, Marra C, Paolucci S. Relation between depression after stroke, antidepressant therapy, and functional recovery. Journal of neurology, neurosurgery, and psychiatry. 2001;71:258-61.
26. Politi P, Sciarini P, Lusignani GS, Micieli G. [Depression and stroke: an up-to-date review]. Epidemiologia e psichiatria sociale. 2006;15:284-94.
27. Paolucci S, Gandolfo C, Provinciali L, Torta R, Toso V. The Italian multicenter observational study on post-stroke depression (DESTRO). Journal of neurology. 2006;253:556-62.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-5241103EnglishN2018February1HealthcareAlbendazole Resistant Neurocysticercosis- Rare Unusual Case Report
English0709Rattilal MeenaEnglish Ankur MittalEnglish Neera SamarEnglish Mehul PrajapatiEnglishA 25 years old female patient presented with history of recurrent seizures since 2 years. Patient was diagnosed as a case of Neurocysticercosis based on Magnetic resonant imaging (MRI) of brain finding in January 2015 for which she was given a course of Albendazole, Prednisolone and antiepileptic medications. During the following 2 year period, patient developed recurrent seizures and abnormal behavior for which patient was investigated and new neurocysticercosis lesions were found in MRI Brain despite previous complete antiparasitic treatment and adherence to diet and antiepileptic medication. Patient had received courses of Albendazole (4 times) with combination of Ivermectin (1 time), and with course of Praziquantel (1 time). So we are reporting this rare case of neurocysticercosis resistant to conventional, routinely used antihelminthic medications.
EnglishNeurocycticercosis, Albendazol resistance, Praziquantel, Seizure, AntihelminthicINTRODUCTION
Cysticercosis caused by larval stage of the tapeworm Taenia solium, is a major public health problem, both in resourcepoor as well as western developed countries. It is the single most common cause of epilepsy in the resource-poor endemic regions of the world including most of South and Central America, India, South-east Asia, China and sub-Saharan Africa1,2. Humans are only definitive host of Taenia solium harboring the adult tapeworm in the intestine. Both humans and pigs act as intermediate hosts and harbour Taenia solium
larvae in different internal organs including the brain. Humans and pigs acquire cysticercosis through ingestion of eggs excreted in faeces of human carriers. Taenia solium infection is also being increasingly diagnosed in western, affluent countries because of human migration from, and travel to endemic areas. It is common in communities where pigs roam freely and people consume undercooked pork3. Neurocysticercosis is central nervous system (CNS) infection with Taenia solium. It is perhaps the commonest parasitic infestation of the CNS, and has received attention in the last two decades because of the availability of MRI and CT scanning in the countries where cysticercosis is endemic.
CASE HISTORY
25 years old, 54 kg, female presented with history of focal seizures in January 2015. Patient had no any other history like fever, head trauma, chronic cough, Tuberculosis. Patient had history of recent first trimester abortion. Past and Family history were not significant. Patient was mixed by diet eating non-vegetarian diet most of the days in month and had poor hygiene. On examination, patient had unremarkable general and systemic examinations except Fundus showing bilateral papilloedema. Patient’s routine investigations were also within normal limit including blood sugar and serum electrolytes. Stool examination for ova and cyst was negative. T.solium antibody test was positive. Chest X-ray was normal. Mountox test was negative. HIV and VDRL were non
reactive. MRI Brain suggestive of disseminated numerous subcentimeter sizes cystic lesions in bilateral cerebral hemisphere, cerebellar hemisphere, basal ganglia and midbrain with eccentric scolex. Most lesions showing perilesional edema and few lesions showing ring enhancement on post contrast study. Few lesions were calcified. These findings were suggestive of various stages of neurocysticercosis. So we gave to patient a course of Tab Albendazole 400mg BID for 4 weeks with Tab Prednisolone 40mg daily with tapering doses and antiepileptic medication (first course).
This patient again developed focal seizures in July 2015. Patient’s adherence about diet and medication was checked to which she was properly adhered. MRI Brain was again done which was suggestive of various stages of neurocysticercosis. So we again gave Tab Albendazole 400mg BID for 4 weeks under cover of steroid to the patient (second course). In September 2016, this patient again developed headache and altered behavior. Patient’s MRI Brain showed various stages of neurocysticercosis. So patient was given a course of Tab Albendazole 400mg BID for 4 weeks with Tab Ivermectin 12mg daily for 15 days (third course).
Again in February 2017, patient presented with parosmia, abnormal behavior and focal seizure. Repeated MRI Brain showed various stages of neurocysticercosis with colloid vesicular stage with perilesional vasogenic edema in right frontotemporal and parietal region. Extraocular muscles were spared. We planned biopsy of brain lesion to rule out Tubercular granuloma but patient did not give consent for the same. As patient had active neurocysticercosis, patient was given a course of Tab. Praziquantel 900mg. TID (50mg/
kg body weight / day) with Tab Albendazole 400mg BID for 4 weeks (fourth course). Anti-epileptic drug was continued. On may 2017, patient came back for follow up, she was asymptomatic, MRI brain revealed clearance of almost all neurocysticercosis lesions and patient desire to stop all the drugs for future. Now she is living seizer free life without any medications.
DISCUSSION
Despite receiving proper antihelminthic treatment, patient had persistent symptoms and lesions of neurocysticercosis in brain. This is a rare case of albendazole resistant neurocysticercosis This patient has fulfilled the diagnostic criteria for human cysticercosis. Presence of 1 absolute criterion out of 3 is required for a definitive diagnosis as proposed by Del Brutto et al4 i.e. Cystic lesions containing the characteristic scolex
on CT or MRI Brain. Other 2 absolute criteria are demonstration of cysticerci by histologic or microscopic examination of biopsy material, and visualization of the parasite in the eye by fundoscopic examination. These other 2 criteria were not met in our patient.
CONCLUSION
Neurocysticercosis is one of the common helminthic condition of the brain presented with seizure. And Albendazole is used as a drug for neurocysticercosis world wide particularly in developing countries. Although resistance of cysticercosis to Albendazole in humans has been reported in literature very rarely it may occur though5. So this case is most unusual.
ACKNOWLEDGMENT
Authors are thankful to Dr. Savitri Verma- Asst. Professor Obstetrics and Gynecology department, RNT medical college for referring and brought into notice the case to medicine department for management of seizures. 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.
Englishhttp://ijcrr.com/abstract.php?article_id=2429http://ijcrr.com/article_html.php?did=24291. Garcia H H and Del Brutto O H. A Imaging findings in neurocysticercosis; Acta Tropica 2003;87:71–78.
2. Prasad A, Gupta R K. Nath K, Pradhan S, Tripathi M, Pandey C Mand Prasad K N a .What riggers seizures in neurocysticercosis?– A MRI based Study in Pig Farming Community from a District of North India; Parasitol Int 2008;55; 166–171. 3.
3. Prasad K N, Prasad A, Gupta R K, Pandey C M and Uttam S.Prevalence and associated risk factors of T. solium taeniasis in a rural pig farming community of North India; Trans R Soc Trop Med Hyg 2007;101:1241–1247.
4. Del Brutto O. H, V. Rajshekhar, A. C. White Jr, V. C. Tsang, T. E. Nash, O. M. Takayanagui. Proposed diagnostic criteria for neurocysticercosis. Neurology 2001, 57:177-183.
5. Graciela Cárdenas1, Roger Carrillo-Mezo et al. Subarachnoidal Neurocysticercosis non-responsive to cysticidal drugs: a case series. BMC Neurology 2010, 10:16.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-5241103EnglishN2018February1HealthcareManagement of Congenitally Missing Bilateral Lateral Incisors with Fixed Orthodontic Treatment, Ridge Augmentation and Two Stage Implant Therapy: Multidisciplinary Approach – A Case Report
English1014T. RamakrishnanEnglish Saravanan PushparajanEnglish RathnaEnglish R. VijayalakshmiEnglishAim: Placing dental implants in the esthetic zone is considered to be the ultimate challenge for many dentists. Insufficient bone is a common problem for implant placement, especially in the upper anterior jaw. A multidisciplinary approach towards the replacement of congenitally missing lateral incisors was planned.
Case Report: Orthodontic treatment was done to create adequate space to place implant in relation to upper right and left lateral incisors. Insufficient ridge width was confirmed by a computerized tomography scan in relation to 22 region, which was augmented at the time of implant placement. Two stage implant was placed in relation to upper right and left lateral incisors. Permanent restoration was placed after 4 months.
Conclusion: This case report describes esthetic and functional outcomes obtained by the multidisciplinary approach for the restoration of congenitally missing maxillary left and right lateral incisor areas.
EnglishDental Implants, Orthodontics, Ridge AugmentationINTRODUCTION
The successful use of dental implants to replace missing teeth has been one of the most “exciting and evolving areas of clinical dentistry”this decade1. At a time when esthetic dentistry has gained prominence, permanent solutions such as implants have become optimal esthetic treatment options.1,2 While implants have expanded restorative treatment options, treatment planning has become more complex for the dental practitioner and an interdisciplinary team approach is recommended. 2,3 The need for replacing missing teeth involves an interdisciplinary approach with Orthodontist, Periodontist and Prosthodontist. 4 The prevalence of congenitally missing lateral incisor constitutes 5% of the population. It has also been found that the agenesis of both lateral incisors is more common than the agenesis of one lateral incisor (Stamation and Symons 1991). Females are found to be more affected than males (Bergstom 1977, Rolling 1980, Brook 1984, Aashem&Oganard 1993). Treatment alternatives for restoring edentulous spaces resulting from congenitally missing laterals include removable partial dentures, conventional fixed partial denture, resin-bonded bridges, repositioning of canines orthodontically to close the edentulous space and single-tooth implant. 5 Although adjacent teeth may have to be repositioned orthodontically to create space for an implant, implants do not necessitate “altering”or “removing”parts of the natural dentition and are therefore the most conservative options for replacing missing lateral incisors.5-7 In most instances due to the absence of the lateral incisor there is an absence of any functional stimulus for the alveolar expansion to occur resulting in a thin or knife edged alveolar ridge, which may not ideally support an implant. Ridge augmentation procedure is mandatory in many such situations, which can be performed before or during the placement of the implant as per the indication of the individual patient need. Implants can also maintain the alveolar ridge, enhance occlusal function and provide optimal esthetics. This procedure is more favourable since most of the patients are in the adolescent stage with good bone texture.5,8
Success of these implants depend on good evaluation and assessment of bone at the implant site. With hard and soft tissue grafting procedures that are available, implant prognosis rate as well as final esthetic outcome has become increasingly predictable.
CASE REPORT
A female patient aged 21 years, was found to have congenitally missing bilateral maxillary lateral incisors, with spacing between maxillary canine and central incisor, midline diastema was also evident due to tooth material deficiency.
A full set of orthodontic records comprising of study casts, radiographs and clinical photographs were taken for the routine investigation procedure. Participating clinicians (the Orthodontist, Periodontist, Prosthodontist) determined the patients treatment plan collaboratively and communicated throughout the course of the treatment to ensure all the aspects of the treatment are considered and the overall treatment objectives achieved.
The role of the Orthodontist is vital as the space needed for the implant placement in the lateral incisor had to be accurately assessed, by model analysis. The space needed had to be created, by closing the midline diastema, as well as the roots of the maxillary canine and maxillary incisors had to be up righted in order to avoid hindrance during implant placement. Ridge dimension needed for implant placement is 10 mm height and 6 mm width9. Adequate space for the implant is also required between the adjacent roots, ideally they should be parallel to each other. The golden proportion should be considered: one lateral incisor is equal to twothirds of a central incisor. Although, when implants are part of the treatment plan, their size dictates the amount of space that needs to be opened.
On examination, patient presented a pleasant profile and was classified as dento-alveolar class I malocclusion intra-orally, owing to which a nonextraction treatment strategy was adopted. The space required was estimated using Bolton’s analysis which is considered a reliable method. The estimated space for each lateral incisor was 5.9 mm. 0.022 MBT system was used to align and create the space that was calculated. Orthodontic treatment was carried out methodically followed by the prescribed sequence of wires. The permanent central incisors and canines were positioned ideally considering the appropriate root positions for the easy placement of the implant. The patient was under passive state oforthodontic treatment during placement of the implant.
IMPLANT PLACEMENT
Bone growth should be completed at the time of implant placement. Since the alveolar bone formation and adjacent teeth eruption continues there are chances of anterior open bite, if implant placement is done prior to completion ofalveolar bone growth. In this case, implants were placed 18 months after the commencement of orthodontic treatment and sufficient bone width was achieved for the implant. A computer tomography was taken to assess the amount of bone in the edentulous area. Transgingival probing was done prior to placement of implants which showed a width of bone in the upper left lateral incisor region to be 7 mm and upper right lateral incisor region to be 5 mm. Surgical templates were prepared to guide the placement of implants. The implant was placed bilaterally using an open flap technique. Two implants were placed, one with a diameter of 3.3 mm and length of 13mm and the other with the diameter of 3.3 mm and length of 11.5mm. After placing the implant, dehiscence was seen in relation to maxillary right incisor region. A bone graft [Bio-Oss] was placed over the implant along with a GTR membrane. The flap was sutured using 4-0 silk sutures. The appliance was consolidated and maintained in a passive state to promote good healing of the implant site.
DISCUSSION
The prevalence of congenitally missing lateral incisor constitutes 5% of the population. When there is a family history of congenitally missing teeth, asymmetric loss of primary teeth, over-retention of deciduous lateral incisors and canines, lack of developmental canine bulge or impacted maxillary canines, the possibility of missing lateral incisors should be immediately investigated. Early investigation is especially important due to the higher association of congenitally missing or peg-shaped lateral incisors with these anomalies. In addition, early investigation will give the patient time to explore all possible treatment options including implant restorations.
Psychological effects of tooth loss are complex and varied and range from minimal to a state of anxiety which significantly affects the social life. Studies done by Mahmoud K et al, 200910 demonstrated that females are more affected by tooth loss in terms of eating and body activity. The number of missing anterior teeth influences patient perception and satisfaction with their dentition. 80% of the patients treated with implant-supported prosthesis were judged for their overall psychological health and showed improved psychological health compared with their previous state of wearing removable dentures or fixed prosthesis. Fixed prosthesis requires support from the adjacent teeth as well there is an increased risk of fracture, loosening or root sensitivity which is a major disadvantage.
Computerized tomography provides cross-sectional radiographic images that facilitate proper assessment of potential recipient sites for implant placement. It offers a precise and detailed evaluation of the height and width of alveolar ridge. The surgical placement of implants is governed primarily by the prosthetic design and secondarily by the morphology and quality of the alveolar bone. Implant placement may be difficult if at all possible due to alveolar ridge aberrations. In consequence, prosthetically dictated dental implant positioning often entails augmentation of the alveolar ridge and adjacent structures. Bio-Oss is a highly biocompatible and osteoconductive material which is slowly resorbed in humans and can be used with success as a bone substitute in ridge augmentation procedures.
CONCLUSION
This case report describes aesthetic and functional outcomes obtained by the multidisciplinary approach for the restoration of congenitally missing maxillary left and right lateral incisor areas and fabrication of two single crowns. In congenitally missing situations, in absence of any pathologic symptoms or negative radiologic findings, such a kind of treatment suggest a successful and a satisfactory result in short-term evaluation.
Englishhttp://ijcrr.com/abstract.php?article_id=2430http://ijcrr.com/article_html.php?did=24301. Mantzikos T, Shamus I. Case report: forced eruption and implant site development. Angle Orthod 1996;68(2):179-86.
2. Schweizer CM, Schlegel AK, Rudzki-Janson I. Endosseous dental implants in orthodontic therapy. Int Dent J 1996;46(2):61-8.
3. Dialogue. The role of the orthodontist on the maxillary anterior implant team. Am AssocOrthodon 1998;10(2):67-9.
4. Bishara SE. Impacted maxillary canines: a review. Am J Orthod- DentofacialOrthop 1992;101(2):159-71.
5. Rupp RP, Dillehay JK, Squire CF. Orthodontics, Prosthodontics and Periodontics: a multidisciplinary approach. Gen Dent 1997;45(3):286-9.
6. Balshi TJ. Osseointegration and Orthodontics: modern treatment for congenitally missing teeth. Int J Perio Rest Dent 1993;13(6):495-5.
7. Cronin RJ, Cagna DR. An update on fixed prosthodontics. J Am Dent Assoc 1997;128(4):425-36.
8. Miller BJ, Taylor NG. Lateral thinking: the management of missing upper lateral incisors. Br Dent J 1995;79(3):99-106.
9. Spear FM, Mathews DM, Kokich VG. Interdisciplinary management of single-tooth implants. Semin Orthod. 1997;3(1):45–72.
10. Mahmoud K Al-Omiri, Jumana A Karasneh, Edward Lynch, Philip-John Lamey, Thomas J Clifford. Impact of missing upper anterior teeth on daily living. Int Dent J 2009;59(3):127-132.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-5241103EnglishN2018February1HealthcarePhysical Attributes as Indicator of Performance for Broad Jumping
English1518Jaskaran Singh SidhuEnglishAim: The Aim of the present study was to identify the talent for standing broad jump with the help of physical attributes.
Methodology: The sample of the present research work was selected from Govt Boys School Mansa of Mansa district (Punjab) a sample of 40 male students were taken 20 from the age group of 10-12 and 20 from the age group of 12-14. Tools-Height was measured by anthropometric rod set to the nearest 0.5cm.
Leg Length: The straight distance between head of the femur and lateral malleolus of fibula. Leg length was measured by anthropometric rod in centimetres to the nearest 0.5cm.
Age: Age of the students was verified from the school record. Standing Broad Jump: The athlete stands behind a line marked on the ground with feet slightly apart. A two foot take-off and landing is used, with swinging of the arms and bending of the knees to provide forward drive. The subject attempts to jump as
far as possible, landing on both feet without falling backwards. Three attempts are allowed. Record the longest distance jumped, the best of three attempts. Steel tape was used to measure the distance and the same was recorded in centimetres to the nearest 0.5cm.
Statistical Analysis: The required data were collected by measuring leg length, Height, Age and standing broad jump. For the statistical analysis the Pearson’s Co-relation statistical technique was employed.
Results: On the basis of findings it was found in the age group of 10-12 years there was moderate positive correlation between standing long jump and leg length, In case of height and age the correlation is positive but weak. In the age group of 12-14 years the correlation between standing broad jump and leg length is positive but weak. The relation of standing broad jump with height and age shows positive correlation but weak relation.
Conclusion: Physical attributes helps in talent identification in children’s..
EnglishStanding broad jump, Anthropometric rod, Leg lengthINTRODUCTION
To achieve and attain top level performance in sports the dimension of body must correspond to the mechanical aspect of game/sports concerned. The success of top level players of the world lies in the selection of sports event according to the structure of sports event at the early stage these athletes have perfect correlation with the event. In developing countries the numbers of sports persons are more than the developed nations but the result are not as per participation the reason being wrong selection of sports events, in developing countries the selection of event is mostly influenced by facilities available in school and nearby no scientific technique is adopted to help the individual to select the sports event according to the structure of the body. While selecting the event most of the children were influenced by peer group, availability of coach, grounds, media and social infrastructure etc. Physical education teacher must bear in mind the growth pattern of students while selecting the game and training because children grow at different rates which affect their performance, many of the physical traits of children are acquired through heredity and influenced by environment so while selecting a sports event one must take these factors into consideration. Talent identification enable long range planning and decisions for top level performance. According to Bompa[1] (1999) there are two methods used for tal--ent identification(a) natural selection (b) scientific selection ‘Natural selection’ is aimed at identifying talented individuals that are already participating within a sport due to the recognition of performance or scouting. As such, ‘natural
selection’ processes rely on talented individuals to ‘happen upon’ the sport they are most likely to excel in even though involvement may result purely from peer or parental interests, proximity of facilities, or of the sport’s popularity in that geographical area. ‘Scientific selection’ processes can be viewed as a more proactive procedure by which identification of the talented occurs as a result of testing individuals on values that are associated with expertise within a certain sport. For example, what are the physical, physiological and psychological attributes that affect performance within football or sprinting? By using scientific research to identify the
criteria that elite athletes possess, and the optimum environment for nurturing these criteria, resources can be targeted at those individuals that have the greatest potential of becoming
outstanding performers. In fact, the early identification of the talented has been highlighted as one of the most important concerns of contemporary sport. Advantages of Using Scientific
Criteria in the Process of Talent Identification are.
1. Substantially reduces the time required to reach high performance by selecting individuals who are gifted in sport
2. Eliminates a high volume of work, energy, and talent on the part of the coach. The coach’s training effectiveness is enhanced by training primarily those athletes with superior abilities
3. Increases competitiveness and the number of athletes aiming at and reaching high performance levels. As a result, there is a stronger and more homogenous national team capable of better international performance
4. Increases an athlete’s self confidence, because his or her performance dynamics are known to be more dramatic than other athletes of the same age who did not go through the selection process.
5. Indirectly facilitates applying scientific training, because sport scientists who assist in talent identification can be motivated to continue to monitor athletes training.
In jumping events leg power is required for that the size and structure of the jumper plays important role for high end performance so a right kind of athlete be selected for the event. Wakai and Linthorne [3]in (2005) found in their study that body dimensions may significantly affect performance when Standing Broad jump is used for the assessment of leg muscle power in children, since taller individuals may jump longer than shorter ones with the same leg muscle power. The most important factors for this outcome are the higher centre of mass and the longer leg length in taller children, which increase the trajectory of the centre of mass and thus Standing Broad jump performance. In the present study we will identify the jumping abilities among the school children’s by measuring body dimension and through broad jump testing, which help the students to know their abilities and helps the students to select the sports event it also help the coaches to train the children according to their potential.
Aim of the Study: The purpose of this study is to identify the talent among school children’s and help them to select the sports event according to their physical attributes.
Methodology
Sample- The sample of the present research work was selected from Govt Boys School Mansa of Mansa district (Punjab) a sample of 40 male students were taken 20 from the age group of 10-12 and 20 from the age group of 12-14.The subjects were selected randomly.
Statistical Analysis – To find the correlation between the variables the data on Broad Jump, Leg Length and Height were analysed by applying Carl Pearson correlation. The discussion
and analysis will reveal the results in the following tables.
Tools
Height- The anthropometric rod was used for measuring height. The subjects were made to stand bare footed against a wall with his heels, buttocks, and upper back and back of head in contact with the wall. The heels were touching each other and head was so held that the Frankfurt plane was horizontal. Arms were hanging down on the sides. The anthropometric
rod was held vertically and the horizontal arm was brought so that it touched the highest point on the head in the mid saggital section (vertex). Height was taken without socks. Height was recorded to 1/10 of a centimetre.
Leg Length: The straight distance between head of the femur and lateral malleolus of fibula. Leg length was measured by anthropometric rod in centimetres to the nearest to 1/10
of a centimetre.
Age- Age of the students was verified from the school record.
Standing Broad Jump- The athlete stands behind a line marked on the ground with feet slightly apart. A two foot take-off and landing is used, with swinging of the arms and bending of the knees to provide forward drive. The subject attempts to jump as far as possible, landing on both feet without falling backwards. Three attempts are allowed. Record the longest distance jumped, the best of three attempts. Steel tape was used to measure the distance and the same was recorded in centimetres to the nearest 0.5cm.
Results of the Study
As evident from table 1, In the age group of 10-12 years the mean of leg length 0.76 and mean value of standing broad jump is 1.422 shows a moderate positive correlation having R value 0.5161, indicating that with the increase of leg length the standing broad jump increase. Paul Pradip Kumar[ 8] (2013) Xavier Maria Raj[15](2017) supports the results of the above study. A weak correlation exist between height having mean value of 1.39 and Standing Broad jump having mean value of 1.422 and value of R is 0.0338 indicating weak positive correlation, the results indicates that performance in standing broad jump is not strongly affected by height. Joshi Deepti and Kumar Ajay[12] (2016) support the results of the above study. In case of Age and standing broad jump the value of R is 0.4396. Although technically a positive correlation, the relationship between age and standing broad jump is weak having mean value of age 11.22 and standing broad jump 1.422, indicates that age has no direct impact on the performance standing broad jump.
From the above table-2 in the age group of 12-14 although technically a positive correlation exist between leg length and standing Broad jump having value of R is 0.2441 and having leg length mean value of 0.838 and standing Broad jump mean 1.57,5 but the relationship between variables is weak, shows that performance in standing broad jump is not dependent on leg length. The correlation between height and standing Broad jump is technically a positive correlation having R value 0.2224 the mean value of height is 1.45 and of standing Broad jump is 1.575 but the relationship between height and standing Broad jump is weak, the results indicates that height is not the criterion for the performance of standing Broad jump, the study conducted by Veligekas Panayiotis, Tsoukos Athanasios, & Bogdanis Gregory C[7] (2012) were also of the opinion that broad jump is not affected by leg length and height . In case of age and standing Broad jump having mean value of 12.671 and 1.575 respectively, having value of R 0.0208 technically showing positive correlation but the relationship between age and standing Broad jump is weak, indicating that with the increase in age the performance in standing Broad jump does not increase.
DISCUSSION
The results of the present study showed that in the age group of 10-12 years the leg length had a moderate correlation with standing broad jump. The relationship of height with standing
broad jump is positive but weak in nature. In case of age its relation with standing broad jump had positive correlation but weak in nature. In age group of 12-14 years the correlation between leg length and standing broad jump is technically positive but weak. In the category of height and age the relationship with standing broad jump shows positive correlation but weak in nature. From the above results it is evident that parameters like leg length, height and age
had less impact on the performance of standing broad jump. The performance in standing broad jump depends on many factors like leg muscle mass, length of lower leg, length of upper leg, dimension of foot, centre of gravity, acceleration abilities of limbs, approach angle, takeoff angle, landing technique, approaching speed, leg power, kinanthopometric measurements of body, body mass index and some other biomechanical factors. As the sample taken for the study is of growing age and the aim of our study is to identify the talent among children’s, only three variables were studied so to find evidence of their impact on the performance of standing
broad jump, determining these factors as indicator of performance is premature at this stage. Wider factors must be stud-ies to find out the talent among the teenagers to help them to choose sportive event according to their body dimensions and capabilities.
CONCLUSION
The following conclusions were drawn from the present study. In the age group of 10-12 years moderate positive correlation exist between leg length and standing broad jump. A weak positive correlation exists between height, age and standing broad jump. In the age group of 12-14 years a weak positive correlation exists between leg lengths, height, age and standing broad jump. Hence we came to conclusion that physical attributes helps in talent identification in children’s.
ACKNOWLEDGEMENT
I am thankful to the staff and physical education teacher of Govt School for boys Mansa for their cooperation to complete this research work. I am also thankful for 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: NA
Englishhttp://ijcrr.com/abstract.php?article_id=2431http://ijcrr.com/article_html.php?did=24311. Bompa, T. O. (1999). Periodization. Theory and methodology of training (4th ed.). Champaign, IL: Human Kinetics.
2. Seyfarth A, Blickhan R, And Van Leeuwen J. L (2000) Optimum Take-Off Techniques And Muscle Design For Long Jump. The Journal of Experimental Biology.Vol 203, 741–750.
3. MI Wakai and NP Linthorne(2005). Optimum take-off angle in the standing long jump. Human Movement Science,Vol; 24(1): 81–96.
4. Wyon Matthew, Allen Nicolas, Angioi Manuela, Nevill Alan and Twitchett Emily (2006). Anthropometric Factors Affecting Vertical Jump Height in Ballet Dancers. Journal of Dance Medicine & Science. Volume 10, Numbers 3 and 4.
5. Mati? Milan, Mrdakovi?, Vladimir, Jankovi? Nenad, Ili?,Duško Stefanovi? ?or?e and Kosti? Saša (2012). Active Landing and Take-Off Kinematics of The Long Jump. Physical Education
and Sport Vol. 10, No 3, PP 243–256.
6. Sisodiya Aman Singh, Singh Sudha and Rathore Neelu (2012). Relationship of Female Selected Anthropometric Variables To Jumping Ability. International Journal of Behavioural Social and Movement Sciences Vol.01, Issue 03.
7. Veligekas Panayiotis, Tsoukos Athanasios and Bogdanis Gregory C.(2012) Determinants of Standing Long Jump Performance In 9-12 Year Old Children. Serbian Journal of Sports Sciences. Vol 6(4): 147-155.
8. Paul Pradip Kumar (2013). Comparative Study on Leg length and Leg Explosive Strength of 12-16 Years Boys. International Journal of Physical Education, Fitness and Sports| Vol.2. No. 4.
9. Béres Sándor, Csende Zsolt, Lees Adrian and Tihanyi József (2014). Prediction of Jumping Distance Using A Short Approach Model. Kinesiology.Vol 1:88-96.
10. Pandey Anurag (2014). Relationship of Kinematic Variables with the Performance of Standing Broad Jump. IOSR Journal of Sports and Physical Education. Volume 1, Issue 6.
11. Saiyed Mohemed Zubeir, Pais Veena, Shaikh Afshan, Shemjaz Arakkal Maniyat and Pais Sudeep (2015). Relationship Of Limb Girth, Segmental Limb Length, Hamstring Flexibility
With Vertical Jump In Male Sports Players. International Journal of Current Research and Review. Vol 7 issue 4.
12. Joshi Deepti and Kumar Ajay (2016). Indian Journal of Physical Education, Sports Medicine And Exercise Science. Vol - 16 (1& 2 Combined) Page 16-18.
13. Karmokar Proloy and Khatua Jayanta Kumar (2016). Relationship of leg length foot length and leg strength on young male. International Journal of Applied Research. Vol 2(6): 39-40.
14. .Kuldip and Kumar Sunil (2016). Correlated study of weight and liner measurements with explosive leg strength of Kabaddi players.International Journal of Physical Education, Sports and Health. Vol 3(1): 158-160.
15. Yadav Mahesh and Sardar Sanjit (2016). Comparative Effect of Anthropometric Variables between High and Low Performance on Tribe Long Jumpers. International Journal of Physiology, Nutrition and Physical Education. Vol 1(2): 22-24.
16. Raj Xavier Maria (2017). Relationship Of Selected Anthropometric Measurements And Physical Variables To Performance In Long Jump.. International Multidisciplinary Research Journal Vol 7 Issue 5.
17. Karpodini C.C, M.A. Comoutos Wyon and Koutedakis N., Y (2017). Leg-Length in Relation to Selected Ballet Performance Indicators. Medical Problems of Performing Artists: Volume 32
Number 3: Page 165 (September 2017).
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-5241103EnglishN2018February1HealthcareVirtual Screening and Docking Analysis of Novel Flavonoidanalogues as Antipsoriaticagents
English1927Parakh SharmaEnglish Rohit MishraEnglish Babu VakilEnglishIntroduction: Psoriasis is an immune-mediated chronic, inflammatory skin disease characterized by hyper proliferative keratinocytes and their infiltration into the dermis of T cells, dendritic cells, macrophages and neutrophils. There is ample evidence suggesting the key role of dysregulation of immune cells in the skin, particularly T cells, in the pathogenesis of psoriasis. Calcineurin, a calcium and calmodulin dependent serine/threonine protein phosphatase plays a major role in increasing the production of T cells and thus in the development of psoriasis. Flavonoids such as quercetin and kaempferol are known to inhibit development of psoriasis.
Objective: We have performed docking of novel designed flavonoid analogues of quercetin and kaempferol to Calcineurin by insilicoanalysis to predict their potential as antipsoriatic candidates.
Materials: Eighty analogues each of quercetin and kaempferol were designed using Schrödinger- Maestro 11 and docked with Calcineurin using PyRx software.
Results: The best binding affinities (kcal/mol) were predicted for5 quercetin analogues- Q79 (-6.1), Q78, Q77 andQ76 (-5.9) and Q44 (-4.8) and5 kaempferol analogues-K18, K40 andK44 (-7.6), K3, K48 (-7.5).
Conclusion: This study using PyRx software strongly supports the importance of computational approach in drug discovery.
The short listed novel analogues of quercetin and kaempferol follow Lipinski rule of 5, satisfying basic parameters for drug likeliness. QSAR and pharmacokinetic analysis can be deployed in future, to further characterize them. Eventually, most promising analogues can be synthesized and evaluated to verify their actual antipsoriatic activity.
EnglishPsoriasis, Calcineurin, Kaempferol, Docking, PyRx softwareINTRODUCTION
Psoriasis is an immune-mediated chronic, inflammatory skin disease characterized by hyperproliferative keratinocytes and infiltration of T cells in the dermis.[1]Advances in understanding the immune-mediated pathological mechanisms of psoriasis have opened new therapeutic avenues. [2] There are many possible protein targets in psoriasis which can be inhibited and Calcineurin (CaN) is a popular target to suppress the activation of memory CD4+T cells and their proliferation that plays an important role in psoriasis.[3]A class of drugs called calcineurin inhibitors which include compounds like cyclosporin, voclosporin and tacrolimus are already in use clinically.[4] Cyclosporin A (CsA) is known to bind to Nuclear factor of activated T cells (NF-ATc).[5,6] Thus, blocked NF-ATc transport in nucleus, in turn, blocks T-cell pathway leading to antipsoriatic activity.[7] However, extensive use of CsA is restricted by its severe side effects.[8,9]
Herbal drugs are known to have lesser side effects, ease of availability and may lend themselves as potential antipsoriatic moieties.[10] Flavonoids, have been the subject of extensive research and a variety of compounds showing beneficial effects, have been identified.[11,12] Quercetin, a flavonol, has been reported to inhibit the activity of Calcineurin in Human Embryonic Kidney cells 293 (HEK293).[13] Kaempferol, another flavonol, has also been identified as a novel calcineurin inhibitorin Jurkat cell line model.[14] Therefore, there is for exploring such flavonoids and their analogues for more potent antipsoriatic activity.
Virtual screening(VS), a process of computationally analyzing large compound libraries, to discover new drugs, has become increasingly popular tool in drug discovery research wherein the number of methods and software which use the ligand/target approach is increasing at a rapid pace.[15] The energy function that evaluates the binding free energy between protein and ligand is known as a scoring function. The steps include protein structure preparation, ligands database preparation and docking calculations.[15,16] Determining protein surface atoms and site points as well as assignment of interaction data are sometimes, internally included in the docking software like in PyRx, Schrödinger-Maestro 11 or Discovery Studio.[17]The best ligand hits are predicted by computational approaches that ‘dock’ library of ligands into the structures of target proteins and ‘score’ their potential complementarities to binding sites.[18]
The objective of the present work was to predict promising new flavonoid analogues of kaempferol and quercetin as antipsoriatic agents that will specifically bind to the target protein
calcineurin.[19]The study was performed using Maestro-11 for docking analysis.[15,17,20] The most promising predicted analogues then can be synthesized and evaluated using in vitro/in vivo testing methods. Currently there are very few effective drugs available for treatment of debilitating and life devastating disease psoriasis and work reported here is an attempt to fulfill the urgent need to identify more potent analogues of phytochemicals.[20]
MATERIALS AND METHODS
Selection of Calcineurin protein and optimization Protein calcineurin Protein Data Bank (PDB)ID: 1MF8 was imported from the PDB (http://www.rcsb.org/pdb) [21] andwas analyzed for its active site by discovery studio visualizer (http://accelrys.com).[22,23,24] The protein preparation wizard was used to correct the imported protein coordinates using Maestro-GUI (Schrödinger Suite).[25,26]The corrections involved adding hydrogen atoms, defining the bond orders, deleting unwanted water molecules and salts followed by optimizing hydrogen bond network. All the atoms in the system were atom-typed using the OPLS2005 force field.[26,27]
The protonation states of titratable amino acid residues were defined at pH 7.4 (physiological state) using PropKatoolin- Schrödinger Suite. For minimizing the protein in explicit water box, appropriate numbers of TIP3P water molecules along with number of ions were added to neutralize the system using Desmond module.
The protein coordinates were optimized in 3 minimization cycles, consisting of 100,000 steps with convergence criteria of 0.001 kcal/mol/Angstrom. First 1000 steps employed steepest descents minimizer and remaining steps used Conjugate- gradients minimizer.[28] The first cycle of minimization placed 25 kcal/mol/Angstrom^2 force constant. This force was reduced to 5 kcal/mol/angstrom^2 and the last cycle of minimization was performed without any restraining potentials for final energy minimization. If the system is unable to relax without any restrains after the last cycle then it is an indication that the system is not a good starting point.[29,30]
Designing and preparation of analogues: The basic structures of quercetin and kaempferol are shown in figure 1and2. The structures were retrieved from Pub Chem database (https://pubchem.ncbi.nlm.nih.gov/).[31]Theirnovel analogues were designed by maestro-11 and saved in MDL files (V2000)and were converted to SDF files used as input in PyRx software.(http://PyRx.sourceforge.net/).[32]
Docking analysis and grid generation: Open Babel tool was used for optimizing designed analogues with forcefields MMFF94 and GHEMICAL. Analogues energy was minimized by Conjugate Gradient and Steepest Descent optimization algorithms. The cycle consisted of 50000 steps with convergence criteria of 0.001 kcal/mol/Angstrom. Finally ‘all ligand’ option was used to convert the minimized files to PDBQT format to generate their atomic coordinates for docking. For docking analysis, the protein1MF8 grid box was set at the retained coordinates of cyclosporin A where center_x = -37.0035159475, center_y = 16.4330071521, and center_z = 24.2216177997.[33] Drug likeliness parameters were predicted by VLIFEMDS-QSARPro (www.vlifesciences. com).[34,35] The best interactions were visualized by Discovery Studio.[22]
RESULTS
The data for parent structure of quercetin (Figure 1-Q80) and its novel designed analogues with functional groups substitution is presented in table 1(A) whereas parent structure of kaempferol (Figure 2-K80)and data for its novel designed analogues are shown in table1(B).[36]
Table 2(AandB) shows docking scores (kcal/mol/Angstrom) retrieved from PyRx software along with parameters of drug likeliness (hydrogen bond donor/acceptor, xlogp and molecular weight) using VLIFEMDS-QSAR Pro. The PyRx software uses a measure of distance between the experimental and predicted structures to compare the accuracy of the predictions. Root mean square deviation are calculated relative to the best mode and using only movable heavy atoms. Two variants of RMSD are lb-lower bound and ub-upper bound, differing in how the atoms are matched in the distance calculation.[32]
Calcineurin protein PDB ID: 1MF8 active site analysis by discovery studio software is depicted in figure3(A)where amino acid residues val314, ala103,tyr341 and trp 352 are interacting with the known antipsoriatic drug cyclosporin A. Next, the newly designed analogues of quercetin and kaempferol from table 1 AandB were then docked at the same active site of calcineurin to predict best analogues binding mode.[33] Top scored quercetin analogues interactions with protein ID: 1MF8 are shown in Figure 3 (B-F) similarly Figure3 (G-K) shows interactions of best kaempferol analogues with 1MF8.
DISCUSSION
Some in vitro studies have shown that flavonoids like quercetin and kaempferol have anti-psoriatic activity against the calcineurin protein.[37] Such reports have shown that best docked analogues of quercetin and kaempferol do have favorable ligand-protein molecular interactions, similar to the interaction of cyclosporin A with calcineurin.[33] In our present docking analysis, datasets of 80 analogues each of kaempferol and quercetin flavonoids were docked at the active site of calcineurin protein using PyRx software. The docking data of ligand-protein molecular interactions for 5 best quercetin analogues namely Q79 (-6.1), Q78, Q77 and Q76 (-5.9) and Q44 (-4.8) and for best 5 kaempferol analogues namely K18,K40 andK44 (-7.6) and K3andK48 (-7.5)are depicted in figure 3(B-F) and (G-K), respectively.
Kartasasmita RE et al, (2010) have performed docking study using Arguslab software on inducible nitric oxide synthase (PDB ID: 1M9T) with quercetin derivatives. They predicted
more potent iNOS inhibitors than parent quercetin, asQuercetin- 3-O-acetate with -10 kcal/mol and 6,8-dichloroquercetin- 3-O-acetate with -7.49 kcal/mol binding score.[38]
Zaveri et al (2015) showed that the target protein- Deltalactam- biosynthetic de-N-acetylase protein (PDB ID: 2J13), when docked with potential ligands taken from NCI and Drug Bank databases, the best scored ligands were identified as NCI-293778 and Rofecoxib which share the common site residues as that of residues predicted in CASTp tool binding pocket predictor. [33]
From the drug likeliness analysis shown in table 2 (AandB) it becomes evident that the best analogues are in the acceptable range by Lipinski rule of 5[35] and may have similar pharmacological properties like parent structures of quercetin and kaempferol. It is hoped that some of them may possess better antipsoriatic activity.[3,5] Dash R (2015) has revealed that when docking was performed with COX-2 protein and the 12 natural flavonoids compounds, afavorable binding energy of > -8 kcal/mol in ArgusLab docking software was predicted [39]Sharma and Vakil(2017)using2D QSAR method by VLIFEMDS-QSARpro software, have predicted antipsoriatic activity for some novel analogues of quercetin and kaempferol.[40]
In line with the above discussion related to usefulness of docking studies, our work, using PyRx software, has predicted and confirmed that some novel analogues of quercetin which show similar binding scores as parent structure and kaempferol analogues too have better binding score compared to parent structure. These analogues do show favorable
drug likeliness properties and bind to the same active site of target protein calcineurin where drugs like cyclosporin A are known to bind.
CONCLUSION
This study performed with PyRx software strongly supports the importance of computational approach in early part of drug discovery research. It results in saving enormous amount of time, resources and money. The novel quercetin and kaempferol analogues follow Lipinski rule of 5. In future, 3D QSAR studies coupled with pharmacokinetic analysis can validate predicted potential of these antipsoriatic agents. Most promising analogues can be synthesized in vitro and tested on human keratinocyte cell lines and if results are satisfactory, it may prove to be rewarding experience in terms of finding more potent antipsoriatic agents.
ACKNOWLEDGMENT
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: External funding –Nil. Internally .financed by the college
Englishhttp://ijcrr.com/abstract.php?article_id=2432http://ijcrr.com/article_html.php?did=24321. Cai Y, Fleming C, Yan J. New insights of T cells in the pathogenesis of psoriasis. Cellular and molecular immunology. 2012 Jul 1;9(4):302-9.
2. Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Annals of the rheumatic diseases. 2005 Mar 1;64(2):30-36.
3. Sieber M, Baumgrass R. Novel inhibitors of the calcineurin/ NFATc hub-alternatives to CsA and FK506?. Cell Communication and Signaling. 2009 Oct 27;7(1):25-44.
4. Khurana A, Brennan DC. Current concepts of immunosuppression and side effects. In Pathology of solid organ transplantation 2009. Springer Berlin Heidelberg.2(1):11-30.
5. Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes and development. 2003 Sep 15;17(18):2205-2232.
6. Bronstein-Sitton N. T cell signalling and activation: no simple matter. Pathways. 2006;2:8-11. 7. Tedesco D, Haragsim L. Cyclosporin: a review. Journal of transplantation. 2012 Jan 4;(2012):1-7.
8. Berger TG, Duvic M, Van Voorhees AS, Frieden IJ. The use of topical calcineurin inhibitors in dermatology: safety concerns. Journal of the American Academy of Dermatology. 2006 May
1;54(5):818-823.
9. Johnson-Huang LM, Lowes MA, Krueger JG. Putting together the psoriasis puzzle: an update on developing targeted therapies. Disease models and mechanisms. 2012 Jul 1;5(4):423 433.
10. García-Pérez ME, Stevanovic T and Poubelle PE . New therapies under development for psoriasis treatment. Current opinion in pediatrics,2013; 25(4):480-487.
11. Geetha M. Anti-psoriatic activity of flavonoids from Cassia tora leaves using the rat ultraviolet B ray photodermatitis model. RevistaBrasileira de Farmacognosia. 2014 Jun;24(3):322-329.
12. Vijayalakshmi A, Geethab M and Ravichandiran V. Anti-Psoriatic Activity of Flavonoids from the Bark of Givotiarottleriformis Griff. Ex Wight. Iranian Journal of Pharmaceutical Sciences, 2014; 10 (3): 81- 94.
13. Zhao X, Wang Q, Yang S, Chen C, Li X, Liu J, Zou Z, Cai D. Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer. European journal of pharmacology. 2016 Jun 15;781:60-68.
14. Kaidama WM, Gacche RN. Antiinflammatory activity of Quercetine in acute and chronic phases of inflammation in Guinea pigs. American Journal of Phytomedicine and Clinical Therapeutics. 2015 Feb 27;3(2):129-136.
15. Lavecchia A, Di Giovanni C. Virtual screening strategies in drug discovery: a critical review. Current medicinal chemistry. 2013 Aug 1;20(23):2839-2860.
16. JE MA, MN A. Virtual screening and lead optimisation to identify novel inhibitors for HDAC-8. arXiv preprint arXiv: 1209.2793. 2012 Sep 13:1-58.
17. Lionta E, Spyrou G, K Vassilatis D, Cournia Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Current topics in medicinal chemistry. 2014 Aug 1;14(16):1923-1938.
18. Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nature reviews Drug discovery. 2004 Nov 1;3(11):935- 949.
19. Varadwaj PK, Sharma A, Kumar R. An overview of psoriasis with respect to its protein targets. Egyptian Dermatology Online Journal. 2010 Jun 1;6(1):1-13.
20. Asgaonkar KD, Mote GD, Chitre TS. QSAR and molecular docking studies of oxadiazole ligated pyrrole derivatives as enoyl-ACP (CoA) reductase inhibitors. Scientia pharmaceutica. 2013 Nov 24;82(1):71-86.
21. Protein Data Bank (PDB): database of three-dimensional structural information of biological macromolecules. Acta Crystallographica Section D: Biological Crystallography, 54(6):1078-
1084.
22. Sussman JL, Lin D, Jiang J, Manning NO, Prilusky J, Ritter O, Abola EE. Protein Data Bank (PDB): database of three-dimensional structural information of biological macromolecules. Acta Crystallographica Section D: Biological Crystallography. 1998 Nov 1;54(6):1078-84.
23. Jamal QM, Lohani M, Siddiqui MH, Haneef M, Gupta SK, Wadhwa G. Molecular interaction analysis of cigarette smoke carcinogens NNK and NNAL with enzymes involved in DNA repair pathways: An in silico approach. Bioinformation. 2012;8(17):795-800.
24. Kishore DP, Maillabaram R, Rao AR, Rao PM. Antiinflammatory Evaluation and Docking Studies of Some New Thienopyrimidines. Asian Journal of Chemistry. 2013 Dec 11;25(18):10583- 10587.
25. Maestro 11: A drug designing suite of Schrödinger: Available at https://www.Schrodinger.com/maestro 2005. Accessed on 17 August 2017, 2:09 pm.
26. Banerjee K, Gupta U, Gupta S, Wadhwa G, Gabrani R, Sharma SK, Jain CK. Molecular docking of glucosamine-6-phosphate synthase in Rhizopusoryzae. Bioinformation. 2011;7(6):285- 290.
27. Srinivasan P, Chella Perumal P, Sudha A. Discovery of novel inhibitors for Nek6 protein through homology model assisted structure based virtual screening and molecular docking approaches. The Scientific World Journal. 2014 Jan 22;2014:http:// dx.doi.org/10.1155/2014/967873
28. Suvannang N, Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul V. Molecular docking of aromatase inhibitors. Molecules. 2011 Apr 28;16(5):3597-617.
29. Jyoti K, Bhatia RK, Martis EA, Coutinho EC, Jain UK, Chandra R, Madan J. Soluble curcumin amalgamated chitosan microspheres augmented drug delivery and cytotoxicity in colon cancer cells: In vitro and in vivo study. Colloids and Surfaces B: Biointerfaces. 2016 Dec 1;148:674-683.
30. S Chintakrindi A, AF Martis E, J Gohil D, T Kothari S, S Chowdhary A, C Coutinho E, A Kanyalkar M. A Computational Model for Docking of Noncompetitive Neuraminidase Inhibitors and Probing their Binding Interactions with Neuraminidase of Influenza Virus H5N1. Current computer-aided drug design. 2016 Dec 1;12(4):272-281.
31. PubChem database, 2004: Available at https://pubchem.ncbi. nlm.nih.gov/, Accessed on 5 August 2017, 11:56 am.
32. PyRx tool: Docking analysis tool,2009: Available at http://PyRx. sourceforge.net/, Accessed on 15 September 2017, 10:52 am.
33. Zaveri K, Chaitanya AK, Reddy IB. Virtual screening and docking studies of identified potential drug target: Polysaccharide deacetylase in Bacillus anthracis. International Letters of Natural Sciences. 2015;7(34):70-77.
34. VLIFEMDS Integrated platform for computer aided drug design (CADD), 2008. Available at : http://www.vlifesciences.com/ products/VLIFEMDS/Product_VLIFEMDS.phph, Accessed on 6 September 2017, 9:15 am.
35. Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies. 2004 Dec 31;1(4):337-341.
36. Materska M. Quercetin and its derivatives: chemical structure and bioactivity-a review. Polish journal of food and nutrition sciences. 2008;58(4):407-413.
37. Vijayalakshmi A, Ravichandran V, Velraj M, Nirmala S, Jayakumari S. Screening of flavonoid “quercetin” from the rhizome of Smilax china Linn. for anti–psoriatic activity. Asian Pacific journal of tropical biomedicine. 2012 Apr 1;2(4):269-275.
38. Kartasasmita RE, Herowati R, Gusdinar T. Prediction of their Absorption and Distribution Properties. Journal of Applied Sciences. 2010;10(23):3098-4104.
39. Dash R, Uddin MM, Hosen SZ, Rahim ZB, Dinar AM, Kabir MS, Sultan RA, Islam A, Hossain MK. Molecular docking analysis of known flavonoids as duel COX-2 inhibitors in the context of cancer. Bioinformation. 2015;11(12):543-549.
40. Sharma P K and Vakil B V. Predictive QSAR analysis of flavonoid analogues as antipsoriatic agents. International journal of pharmaceutical sciences and research. 2017; 8(12): 1000-1014.