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JOURNAL OF INTERNAL MEDICINE OF INDIA • AUG. - OCT. 2018 • VOL. 12 • NO. 3 • RNI No. 69152/98

1© JIMI • AUG. - OCT. 2018 • VOL. 12

ContentsORIGINAL ARTICLE1. Impact of Breakfast on the Nutrients and Metabolic Risk Factors in North Indian Adults 6 D. Himanshu, Saumya Mishra, Sunita Saxena, Neera Verma

2. A Hospital Based Cross - Sectional Study to see the Seroprevalence of Hepatitis B Co-infection in 11 HIV Seropositive Patients

Anita, Shri Krishna Gautam, J.S. Kushwaha, Brijesh Kumar, Dharmender

3. Assessment of CSF CRP/Protein/Glucose to Determine Etiological Agent in CNS Infections 15 Ram Avatance Sharma, M.L. Pursnani, Ravindra Singh Chahar, Nikhil Pursnani,

Prabhat Agrawal, Ashish Gautam

4. Fibromyalgia Linked to Uncontrolled Diabetes Mellitus and Hypomagnesemia 19 J. Fatima, V. Jain, S. Priya, R. Karoli, V. Shukla, Z. Siddiqi, KI Khursheed, A. Kumar,

5. Evaluation of Smokeless Tobacco as a risk factor for Essential Hypertension 26 Smriti Singh

REVIEW ARTICLE6. Current Applications of Nanomedicine in Clinical Fields 30 Amitesh Aggarwal, Ajay Kumar Gupta, Vivek Goswami, SK Mundhra

CASE REPORT7. Allergic Bronchopulmonary Aspergillosis Presenting as a Pulmonary Mass-A Case Report 41 Rajendra Prasad, Anamika Verma, Saurav Pandey, Rishabh Kackar, Jaskirat Singh, Nikhil Gupta

8. Hemorrhagic infarct- A Rare Neurological Outcome of Plasmodium Vivax 46 Cerebral Malaria: A Case Report

A. Pandey, P.K. Maheshwari, M.Chaturvedi

PICTORIAL CME9. Cervical Spondylosis with Reversal of Lordosis – A Pictorial CME 49 A. Pandeya, M.Chaturvedi, P.K. Maheshwari

HISTORY10. Invention of Clinical Thermometer 50 Bhupendra Chaudhary


2 © JIMI • AUG. - OCT. 2018 • VOL. 12

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Subscription InformationUttar Pradesh Journal of Internal Medicine of India (ISSN: 0972-1096). For 2018, Volume 12 (3 issue) is scheduled for publication. Subscription prices are available upon request from UP Journal of Internal Medicine of India or from this Journal website (www.upjimi.com), or contactUP JIMI Customer Service Centre: T-21, Sector-11, Noida-201301 (UP) India. Tel. (0120-4116874, +91 9810210479)E-mail: [email protected] AdvertisementsE-mail: [email protected]

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3© JIMI • AUG. - OCT. 2018 • VOL. 12

GoverningBodyMembers Co-optedMembers

GoverningBodyASSOCIATIONOFPHYSICIANSOFINDIA

UPCHAPTER

GoverningBodyASSOCIATIONOFPHYSICIANSOFINDIA

NOIDACHAPTER

Chairman Dr.KauserUsmanChairman-Elect Dr.VeerendraSinghVice-Chairman Dr.K.K.Sawlani Dr. S. C. ChaudharyHon.Secretary Dr.SanjayTandonTreasurer Dr.D.HimanshuJointSecretaries Dr.S.Chakravorty Dr.NirupamPrakash

Dr.AtulMehrotraDr.AnupamWakhluDr.SandeepChaudharyDr.JaleesFatimaDr.S.K.GautamDr.SmitaGupta

PatronProf. (Dr.) B. C. BansalProf. (Dr.) Om Kumari GuptaDr. S. K. PlahaFormerChairmanDr. Subodh ChandraDr. K.C. SoodDr. G.C. VaishnavaDr. S. ChakravortyChairmanDr. R. K. GattaniViceChairmanDr. G.C. Gupta

SecretaryDr. Meenakshi JainTreasurerDr. A.K. ShuklaJointSecretaryDr. Kuldeep DharProf. (Dr.)Amitesh AggarwalDr. Kiran SethScientificAdvisorDr. Neeru GeraDr. L.K. JhaDr. Amitabh YaduvanshiDr. R.K. PrasadProf. (Dr.) Saurabh SrivastavaDr. Amit Kumar Gupta

CoreCommitteeMemberDr. Sanjay WadhawanDr. Vandana GargDr. Ajay AggarwalDr. N. K. SharmaDr. K.D. KotliaDr. S.K. SahooDr. P.K. GuptaDr. Sanjay MahajanDr. Manju TyagiDr. Vinay LabrooDr. Zeenat Ahmad

Dr.RichaGiriDr.T.P.SinghDr. Jaya ChakrovartyDr.AnubhaSrivastavaDr.AbhaGupta


4 © JIMI • AUG. - OCT. 2018 • VOL. 12

Editorial

“Healthcare is a right and not privilege”Healthcare industry in India is highly fragmented with varying quality of services. The majority of institutions are in private sector. Though public healthcare is either free or heavily subsidised even then people often prefer private hospitals for various reasons. Private hospitals provide better services in various specialized areas. However treatment cost varies hospital to hospital and place to place. Central government has been making continuous efforts to provide health care through 3 tier healthcare institutions and various national health programs. However quality of curative and rehabilitative care has been extremely poor especially in rural area leading to inequality. 6% of people in India do not seek healthcare due to financial reason. The Indian population spends 67% through household out of pocket expenditure (00PE). Health has become a priority for the present government and hence it occupies significant share in the current budget plan3. Ayushman Bharat was launched in the budged speech of 2018. It announced 2 major initiative i.e creation of health & wellness centres ( HWCs) and National Health Protection Scheme (NHPS)1.Health & Wellness Centres & Scheme: A large & comprehensive package of primary healthcare will be delivered at HWCs- which aims to provide preventive, promotive, curative and palliative healthcare. Various facilities such as physiotherapy, yoga room, consultation room, free diagnostics & pharmacy. Elderly health, creation of electronic health records etc are made available. HWCs will continue to play an effective role in all national healthcare programs. HWCs will recruit various medical and paramedical staff in comparison to currently existing facilities in a subcentre.Ayushman Bharat National Health protection Scheme: This is a centrally sponsored scheme which aims to provide annual health cover of upto Rs. 5 lakh to vulnerable 10 crore vulnerable families based on socio-economic & caste status. NHPS provides for pre & post hospitalization expenses as well as transport services2.

April 30, 2018 was observed as Ayushman Bharat Divas when every rural beneficiary was informed about various feature of the scheme.NHPS include health education campaigns, community mobilization and identification of beneficiaries through gram sabhas. NHPS will cover the Rashtriya swasthya Bima Yojana (RSBY) and Senor Citizen Health Insurence Scheme. This scheme, also known as Modicare is the largest state- funded health insurance scheme which drastically reduces out of pocket expenditure and thereby protects 40% vulnerable population from alarming health expenditures.British national healthcare system (NHS) is a social insurance system that operates on the belief that healthcare is a right and not a privilege.In the most basic terms everyone pays in and everyone gets the treatment, but these health plans are not actually free in UK. The system is free at the point of access but paid for through taxation. Whereas in USA healthcare is structural more like privilege than a basic right. One has to be medically insured to avail oneself of healthcare. The indigent depend on non profit hospitals.Ayushman Bharat aims to provide healthcare facilities to over 10 crore families covering urban and rural poor. The scheme offers an insurance cover of Rs 5 lakh, which will cover almost 50 crore citizens making it the biggest healthcare scheme in the world. It is worthwhile to understand the basic models of Healthcare systems to get a sense of how other countries manage healthcare and where could this scheme take usa) The Beveridge model: is the healthcare system

which is provided and financed by the government. In this system, health care is provided and financed by the government through tax payments, just like the police force or the public library. Many, but not all, hospitals and clinics are owned by the government; some doctors are government employees, but there are also private doctors who collect their fees from the government. There is no bill which is given to the patients at the end of

Dear All,It gives me a great pleasure to bring out our first monograph on “Management of Platelet disorders in Clinical Practice” which will provide an in-depth analysis of various platelet disorders, physiology, laboratory assessment, common pitfalls and clinical pearls about platelet related diseases. A section of questionnaire has also been incorporated for the benefit of postgraduates. I hope members will appreciate the effort and help me in bringing out similar monographs in future.


5© JIMI • AUG. - OCT. 2018 • VOL. 12

the treatment and doctors are paid directly by the government. Britain, Spain, most of Scandinavia, Hong Kong and New Zealand follow the Beveridge model.

b) The Bismarck Model: uses an Insurance Scheme usually financed jointly by employees and employers through payroll deduction. Although this model of insurers looks very similar to the US Health system, there are two critical differences. First, under the Bismarck model, insurance companies are bound to cover all citizens and premium is paid by all citizens. This is known as “Universal Health Coverage”. Second the insurance companies in the Bismarck model are non-profit organizations. Whereas the insurers in USA can refuse to accept people based on pre-existing diseases and are for-profit companies. The Bismarck model is found in Germany, France, Belgium, the Netherlands, Japan, Switzerland, and, to a degree, in Latin America.

c) The National Health Insurance Model: has elements from both Beveridge and Bismarck Models. It uses private-sector providers, but payment comes from a government-run insurance program that every citizen pays into. The classic NHI system is found in Canada, but some newly industrialized countries — Taiwan and South Korea, for example — have also adopted the NHI model5.

d) Out of Pocket Model: All countries barring the top 40 developed countries have this system where the healthcare is paid directly at the point of service by the patients. It is no surprise that the poor and the needy are unable to afford quality healthcare in countries which have an Out of Pocket Healthcare model. This has a severe impact on various health indices like life expectancy, infant mortality and quality of life.

70% of healthcare expenses in India are met by out of pocket expenditure by the patient which leaves millions of poor and needy out of the health bracket. Good health and wellbeing is one of the strategic development goals signed by India and all other UN Nations as a target for 2030 and PMJAY is a welcome step in this direction. India ranks 145 among 195 countries on Global Healthcare access and quality (HAQ index) and ranks lower than Bangladesh, Sudan and Guinea. Some states like Uttar Pradesh, Jharkhand and Assam fare worse than the India average and it is only fitting that Government of India launched this scheme from Ranchi. While PMJAY is not the first healthcare insurance scheme launched by Indian government it is certainly

the grandest of all its predecessors. It will provide guaranteed access to treatment that is free at the point of delivery to about 40% of the population selected based on census socio-economic indicators. The implementation of resources therefore needs to be done considering the scale of operations. The allocation of 2000 Crore in the present year towards PMJAY is being considered by many experts as an amount too low and there are valid question marks on the readiness of the healthcare system to handle the unprecedented load that comes with this scheme4. While it remains to be seen if PMJAY will be able to take India to Universal Health Coverage, the sheer emphasis it lays on health protection is unheard of.

References:1. Press Information Bureau Ministry of Finance.

Ayushman Bharat for a New India-2022, Announced [Press Release]: Press Information Bureau, Government of India. 2018. [Last updated on 2018 Feb 01; Last accessed on 2018 Mar 30]. Available from: http://www.pib.nic.in/newsite/PrintRelease.aspx?relid=176049.

2. Press Information Bureau Ministry of Health and Family Welfare. Cabinet Approves the Largest Government Funded Health Program– Ayushman Bharat National Health Protection Mission (NHPM). [Press Release]: Press Information Bureau, Government of India. 2018. [Last updated on 2018 Mar 22; Last accessed on 2018 Mar 31]. Available from: http://www.pib.nic.in/newsite/PrintRelease.aspx? relid=177844 .

3. Union Budget (2018-19) – Department of Health & Family Welfare [database on the Internet] Centre for Budget and Governance Accountability. 2018. [Last accessed on 2018 Apr 02]. Available from: https://www.openbudgetsindia.org/dataset/department-of-health-andfamily- welfare-2018-19/resource/5fca8312-b8a5-45dd-8e82-655d83945a59.

4. Sinha S. Ayushman Bharat May Need Rs. 20,000 Crore Injection in First Year: Insurance Actuaries Mumbai: The Economic Times. 2018. [Last updated on 2018 Mar 23; Last accessed on 2018 Mar 30]. Available from:https://www.economictimes.indiatimes.com/news/economy/policy/ayushman-bharat-may-need-rs-20000-crore-injection-in-first-yearinsurance- actuaries/articleshow/63423513.cms .

5. Singh J. Budget 2016: Health Insurance for All. Live Mint; 201. [Last updated on 2016 Mar 01; Last accessed on 2018 Mar 29]. Available from: https://www.livemint.com/Politics/hQihM87Emz6wxsieuIUZvO/Budget-2016-Health-insurance-for-all.html .


6 © JIMI • AUG. - OCT. 2018 • VOL. 12

Original Article

Impact of Breakfast on the Nutrients and Metabolic Risk Factors in North Indian Adults

D. Himanshu1, Saumya Mishra2, Sunita Saxena3, NeeraVerma4

Abstract:Background : Breakfast is the first meal that provide energy to perform our daily activities. Various studies have shown that skipping breakfast is associated with numerous health issues including overweight ,obesity, type 2 diabetes and metabolic syndrome.[1-3] In many Asian countries, the traditional dietary pattern have changed characterized by low vegetable intake, high intake of animal fats and refined sugar leading to increased risk of obesity and chronic health conditions.[4]Aim : To find out the impact of breakfast on the nutrients and metabolic risk factors in North Indian adults.Method : In the present study we enrolled 153 subjects from the medicine OPD of KGMU and were enquired about their breakfast habits. Subjects were divided into two groups depending on their breakfast habits. Group 1(n=58) were breakfast skippers (S) and Group 2( n=95) were breakfast nonskippers (NS) We compared the waist circumference ,blood pressure, fasting lipid profile and fasting blood sugar levels of both the groups. We also compared calories, protein and fat intake of both the groups by means of 24 hour dietary recall.Result : In this study we found that 37.9% were breakfast skippers (Group 1) and 62.1% were nonskippers (Group 2).In Group 1, 63.8% had metabolic syndrome and in Group 2, 53.7% had metabolic syndrome (p=0.2416).On evaluating the nutrient intake, 20.7% 0f Group 1 and 28.4% of Group 2 were consuming calories above the recommended amount which was not significant statistically (p=0.287).Similarly fat intake was significantly higher in Group 2 (87.4%) as compared to Group 1(55.2%) (p < 0.001).Overall protein intake was low in both the groups,75.9% in Group 1 and 88.4% in Group 2 (p=0.042) which was significant statistically.We also compared the metabolic risk factors and found that mean value of waist circumference was higher in Group 1 as compared to Group 2 (p= 0.564),not significant statistically.Mean value of systolic ( SBP) and diastolic blood pressure( DBP) was higher for Group 1 and was significant statistically (p=0.037) for SBP.We also compared triglycerides (TG) and high density lipoprotein (HDL) cholesterols and found that mean value of TG was higher for Group 1 (p=0.440) and for HDL mean value was higher for Group 2 ( p=0.529 ).Discussion : In our study we found that metabolic risk factors were greater for Group 1 ( S) as compared to Group 2 (NS). Hence prevalence of metabolic syndrome was higher for those subjects who were skipping breakfast (Group 1).

We also found that total calories intake and fat intake was higher for subjects who were breakfast non skippers (Group 2).Overall the above evidence suggests that on limiting the carbohydrate rich diet and fatty diet and consuming the breakfast food high in whole grains and cereal fibres ,is a path for metabolic health promotions.

Thus we conclude that daily breakfast intake and breakfast food high in whole grains and cereal fibres is strongly associated with reduced risk of metabolic syndrome.

1. Associate Professor, Department of Medicine, King George;s Medical University2. Dietician, King George’s Medical University3. Research Officer, Department of Medicine, King George’s Medical University4. Department of Medicine, King George’s Medical University (Corresponding Author)

Email id: [email protected]


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IntroductionMetabolic syndrome (syndrome X, insulin resistance syndrome) is a combination of medical abnormalities, that, when occurring together, increase the risk of developing cardiovascular disease and diabetes mellitus

(1). The major features of metabolic syndrome includes central obesity, hypertriglyceridemia, low HDL cholesterol, hyperglycaemia and hypertension. The criteria for metabolic syndrome became uniform with the establishment of National Cholesterol Education Programme: Adult Treatment Panel III (NCEP: ATP III) and International Diabetes Federation (IDF) guidelines (2,

3). NCEP:ATP III guidelines were formed mainly for the American population however the IDF guidelines takes into account the ethnical variation and difference between male and female.Obesity, a growing health problem all over the world, is an important determinant of metabolic syndrome (4). A rise in the prevalence of obesity has led to an increase in the prevalence of metabolic syndrome also (5).

Almost 30 - 65 % of adult urban Indians are either overweight or have abdominal obesity (6). For many obese patients the risk of developing metabolic syndrome is quite evident but risk of metabolic syndrome increases even in overweight or pre obese individuals (7)Due to our ethnic and regional preferences, dietary pattern is different all over India. There is no structural meal plan i.e. timing of breakfast, lunch and dinner. There is lack of knowledge of how much to eat and how to time those meals. Most of the Indian families skip one meal, mostly breakfast. Breakfast is one of the most important meals of the day, re-fuelling the body with energy and essential nutrients(8,9,10,11)Daily breakfast intake is strongly associated with reduced risk of metabolic conditions.

Various studies have been conducted related to diet, and Metabolic syndrome. One of the study was conducted by Monika Arora et all in the year 2012. It was a cross sectional study done in the students of 8th and 10th Std. of private and gov. schools of Delhi. It was found that prevalence of overweight and obesity among adolescents who consumed breakfast daily (14.6 %) was significantly lower than those who only sometimes (15.2%) or never (22.9%) consumed breakfast. Breakfast consumption was associated with greater physical activity than those who never consumed breakfast (12). Similar findings were seen in a review article by Szajewska H and Ruszczynski M in which 16 studies were identified. All were cross sectional or cohort trials involving more than 59000 adolescents

from Europe. Thirteen studies (n= 57,481) showed that breakfast has a protective effect against becoming overweight or obese. All of these studies showed an increase in BMI in breakfast skippers (13). Another study conducted by Nasreddine L et all in the year March 2014 showed that sedentary life style, higher consumption of fast food and sugar sweetened beverages were associated with increased risk of obesity, overweight and abdominal adiposity, while regular breakfast consumption , higher intake of milk/dairies and added fats/oils were amongst the factors associated with decreased risk (14).

A series of studies have reported that breakfast skipping is associated with Obesity (15), hypertension (16), cardio metabolic disease (17), insulin insensitivity and diabetes mellitus (18).With this background we decided to find out the impact of breakfast skippers on the nutrients and metabolic risk factors in North Indian adults and to find out the impact of breakfast non-skippers on the nutrients and metabolic risk factors in North Indian adults

Study design and methods:It is an observational cross sectional study conducted on subjects from medicine OPD of tertiary care center Lucknow. Subjects were divided into two groups depending on their breakfast (BBF) habits. Group 1 were BBF skippers and Group 2 were BBF nonskippers. Anthropometric measurements and blood pressure were taken and reports of Fasting lipid profile and Fasting blood sugars were noted for both the groups. Total intake of calories, protein and fat were calculated by means of 24 hour dietary recall. Metabolic syndrome was calculated using IDF criteria.

Subjects with age less than 18 years, with history of any chronic disease or history of intake of drugs like steroids, lithium, antidepressant and antipsychotics were excluded.

For sample size for primary outcomes calculation was done taking into consideration a prevalence of overweight and obesity who consumed breakfast daily as 14.6%(12)

and given 1.96 value of the 95% confidence interval and 0.05 was taken as acceptable margin of error and taking into consideration of 10% non-response. The minimum sample size required for the study was 196.

Sample Size = z2 x P x Q ÷ (standard error) 2

Critical value of z = 1.96

Prevalence rate P = 14.6%= 0.15

Q = 1-P = 1-0.15 = 0.85

Standard error = 0.05


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Data Management and Analysis was done using SPSS software edition 16. The total timeline of the study was two months.

Results and DiscussionsIn this study we found that 37.9% were breakfast skippers (Group 1) and 62.1% were non-skippers (Group 2). In Group 1, 63.8% had metabolic syndrome and in Group 2, 53.7% had metabolic syndrome (p=0.2416).On evaluating the nutrient intake, 20.7% 0f Group 1 and 28.4% of Group 2 were consuming calories above the recommended amount which was not significant statistically ( p=0.287).Similarly fat intake was significantly higher in Group 2 ( 87.4%) as compared to Group 1( 55.2%) ( p < 0.001).Overall protein intake was low in both the groups,75.9% in Group 1 and 88.4% in Group 2 ( p=0.042) which was significant statistically.

We also compared the metabolic risk factors and found that mean value of waist circumference was higher in Group 1 as compared to Group 2 (p= 0.564), not significant statistically .Mean value of systolic ( SBP) and diastolic blood pressure( DBP) was higher for Group 1 and was significant statistically (p=0.037) for SBP. We also compared triglycerides (TG) and high density lipoprotein

(HDL) cholesterols and found that mean value of TG was higher for Group 1 (p=0.440) and for HDL mean value was higher for Group 2 ( p=0.529 ).

In our study we found that metabolic risk factors were greater for in skippers as compared to non-skippers even though the net calorie intake was slightly higher among the non-skippers. Hence prevalence of metabolic syndrome was higher for those subjects who were skipping breakfast (Group 1).

We also found that total calories intake and fat intake was higher for subjects who were breakfast non skippers ( Group 2).Overall the above evidence suggests that on limiting the carbohydrate rich diet and fatty diet and consuming the breakfast food high in whole grains and cereal fibres ,is a path for metabolic health promotions. Such findings were also found in previous studies which showed that skipping breakfast does not give any major advantage in controlling metabolic risk factors and specially when compared with a breakfast containing high fiber foods(12,13,14).

Thus we conclude that daily breakfast intake and breakfast food high in whole grains and cereal fibres is strongly associated with reduced risk of metabolic syndrome.

Table 1: Distribution of subjects according to their breakfast habits-

Table 2: Comparison of daily average nutrient intake between two study groups:

Group Description Subjects Percentage

1 Breakfast Skippers 58 37.9

2 Breakfast non-skippers 95 62.1

Serial no.

Nutrient No. of Subjects (n=153)

Group 1 Breakfast Skippers

(n=58)

Group 2 Breakfast Non-skippers(n=95)

Statistical significance

1 High Calorie intake 39 (25.5%) 12 (20.7%) 27 (28.4%) X2=1.133 P=0.287

2 Inadequate Protein intake

128 (83.7%) 44 (75.9%) 84 (88.4%) X2=4.155 P=0.042

3 Fat intake category

Low 12 (7.8%) 10 (17.2%) 2 (2.1%) X2= 21.654P=<0.001Adequate 26 (17.0%) 16 (27.6%) 10 (10.5%)

HIgh 115(75.2%) 32 (55.2%) 83 (87.4%)


9© JIMI • AUG. - OCT. 2018 • VOL. 12

Table 3:Distribution of subjects according to Metabolic Syndrome-

Breakfast Metabolic SyndromeYes No

Number Percentage Number PercentageSkippers (n=58) 37 63.79 44 46.31Non-Skippers(n=95) 51 53.68 21 36.20

Table 4 : Comparison of metabolic risk factors between the two study group

S. No.

Parameters Total Group 1 Group 2 Statistical SignificanceMean SD Mean SD Mean SD

1 WC(cm) 87.33 12.98 88.11 13.51 86.86 12.69 t=0.579; p=0.564

2 SBP(mmHg) 124.26 19.19 128.40 19.04 121.74 18.95 t=2.106; p=0.037

3 DBP(mmHg) 79.37 11.88 80.55 11.72 78.65 11.98 t=0.959; p=0.339

4 TG(mg/dl) 148.54 82.34 155.14 104.17 144.51 65.88 t=0.774; p=0.440

5 HDL(mg/dl) 48.08 11.67 47.32 10.36 48.55 12.43 t=0.631; p=0.529

WC= waist circumference; SBP= Systolic Blood Pressure; DBP= Diastolic Blood Pressure; TG= Triglycerides; HDL= High density Lipoprotein

References: 1. Reaven GM. Role of insulin resistance in human

disease. Diabetes 1988; 37: 1595-607

2. Executive summary of the third report of the National Cholesterol Education Program ( NCEP ) Expert Panel on Detection, Evaluation and treatment of high blood cholesterol in adults ( Adult Treatment Panel III ) , JAMA 2001; 285: 2486-97.

3. The IDF Consensus worldwide definition of the Metabolic Syndrome. International Diabetes Federation. IDF 2006: 10-11.

4. Grundy SM,Brewer HB, Jr.,Cleeman JI et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/ American Heart Association conference on scientific issues related to definition. Circulation 2004; 109(3):433-438.

5. Grundy SM, Hansen B, Smith SC,Jr et al. Clinical management of metabolic syndrome: Report of the National Heart,Lung, and Blood Institute/ American Heart Association conference on scientific issues related to management. Circulation 2004; 109(4):551-556.

6. Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 2008; 93(11 Suppl 1): S 9-30.

7. Vega GL. Obesity, the metabolic syndrome, and cardiovascular disease. Am Heart J 2001; 142: 1108-16.

8. Nicklas T.A., O’Neil C.E., Berenson G.S. Nutrient contribution of breakfast, secular trends, and the role of ready-to-eat cereals: A review of data from the Bogalusa Heart Study. Am. J. Clin. Nutr. 1998; 67:S757–S763.


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9. Ortega R.M., Requejo A.M., Lopez-Sobaler A.M., Quintas M.E., Andres P., Redondo M.R., Navia B., Lopez-Bonilla M.D., Rivas T. Difference in the breakfast habits of overweight/obese and normal weight schoolchildren. Int. J. Vitam. Nutr. Res. 1998; 68:125–132.

10. Rampersaud G. Benefits of breakfast for children and adolescents: Update and recommendations for practitioners. Am. J. Lifestyle Med. 2009; 3:86–103. doi: 10.1177/1559827608327219.

11. Ruxton C.H., Kirk T.R. Breakfast: A review of associations with measures of dietary intake, physiology and biochemistry. Br. J. Nutr. 1997; 78:199–213. doi: 10.1079/BJN19970140.

12. Monika Arora, Gaurang P Nazar, Vinay K Gupta, Cheryl L Perry, K Srinath Reddy, Melissa H Stigler. Association of breakfast intake with obesity, dietary and physical activity behavior among urban school-aged adolescents in Delhi, India: results of a cross-sectional study BMC Public Health.2012; 12:881.

13. Szajewska H, Ruszczynski M. Systematic review demonstrating that breakfast consumption influences body weight outcomes in children and adolescents in Europe. Crit Rev Food Sci Nutr.2010 Feb; 50(2):113-9.

14. O’Neil CE, Nicklas TA, Fulgoni VL 3rd.Nutrient intake, diet quality, and weight/adiposity parameters in breakfast patterns compared with no breakfast in adults: National Health and Nutrition Examination Survey 2001-2008. J Acad Nutr Diet. 2014 Dec;114(12 Suppl):S27-43. doi: 10.1016/j.jand.2014.08.021. Epub 2014 Nov 24

15. Van der Heijden, A.A.; Hu, F.B.; Rimm, E.B.; van Dam, R.M. A prospective study of breakfast consumption and weight gain among U.S. Men. Obesity 2007, 15, 2463–2469.

16. Mogre, V.; Apala, P.; Nsoh, J.A.; Wanaba, P. Ad-iposity, hypertension and weight management behaviours in ghanaian type 2 diabetes mellitus patients aged 20–70 years. Diabetes Metab. Syn-dr. 2016, 10, S79–S85.

17. Shafiee, G.; Kelishadi, R.;Qorbani, M.; Motlagh, M.E.; Taheri, M.; Ardalan, G.; Taslimi, M.; Poursafa, P.; Heshmat, R.; Larijani, B. Association of breakfast intake with cardiometabolic risk factors. J. Pediatr. 2013, 89, 575–582.

18. Mekary, R.A.; Giovannucci, E.; Willett, W.C.; van Dam, R.M.; Hu, F.B. Eating patterns and type 2 diabetes risk in men: Breakfast omission, eating frequency, and snacking. Am. J. Clin. Nutr. 2012, 95, 1182–1189.


11© JIMI • AUG. - OCT. 2018 • VOL. 12

Original Article

A Hospital Based Cross - Sectional Study to see the Seroprevalence of Hepatitis B

Co-infection in HIV Seropositive Patients

Abstract:Background: Human immunodeficiency virus (HIV) and Hepatitis B virus (HBV) are the most common chronic viral infections worldwide. These viruses have similar modes of transmission, mainly through blood and blood products, sharing of needles to inject drugs and sexual intercourse, making co-infection with these viruses a usual event. HBV co-infection in HIV positive individuals is of paramount importance because of the underlying liver related problems associated with these viruses.

Aim: To see the seroprevalence of Hepatitis B co-infection in HIV seropositive patients.

Materials and methods: This study has been conducted at LLR and Associated Hospitals and ART plus centre, GSVM Medical College, Kanpur (UP) from April 2017 to September 2018. This is a hospital-based cross-sec-tional study in which a total of 300 adult male and female HIV seropositive patients of 18 years and above were included. The already diagnosed HIV seropositive patients by HIV testing as per NACO guidelines were investi-gated by ELISA for HBsAg.

Results: In the present study the rate of HBsAg co-infection was 11% (33/300) in HIV seropositive patients. The seroprevalence of Hepatitis B (11%) is similar to the prevalence reported by Saravanan S et al (9%) and Gupta et al (7.28%) but higher than that reported by Tripathi et al (2.25%) and Gupta et al (5.3%).

Conclusion: The main routes of transmission of HIV and HBV are similar, therefore, co-infection with HBV is very likely in HIV infected patients. Therefore, it would be better to screen for this virus in all the HIV infected patients and their sexual partners as early as possible.

Keywords:, Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV) Co-infection.

BackgroundHuman immunodeficiency virus (HIV) and Hepatitis B virus (HBV) are the most common chronic viral infections worldwide. These viruses have similar modes of transmission, mainly through blood and blood products, sharing of needles to inject drugs and sexual intercourse, making co-infection with these viruses a common event. The degree of immunodeficiency becomes an important

factor in the progression of hepatitis among patients co-infected with HBV. HBV co-infection in HIV positive individuals is of significant importance because of the underlying liver related morbidity and mortality associated with these viruses, which have been shown to decrease the life expectancy in the HIV- HBV co-infected patients.Approximately 36.9 million people are living with HIV worldwide at the end of 2017 (WHO). It is estimated that chronic HBV infection affects an estimated 5–20% of people living with HIV. In India, there was an estimated adult (15-49 years) HIV prevalence of 0.22% (0.16 to 0.30%) in 2017. Around 21.4 lac PLHIV (persons living with HIV) were living in the country. Almost 97% of the total PLHIV belonged to the 15+ year’s age group1.HIV and HBV have similar modes of transmission; hence co-infection is common which poses an increased risk for life-threatening complications for people living with both

1. Medical Officer Family Planning, GSVM Medical College, Kanpur (UP)

2. Associate Professor of Medicine, GSVM Medical College, Kanpur (UP) (Corresponding Author) E-mail: [email protected]

3, 4, 5. Professor of Medicine, GSVM Medical College, Kanpur (UP)

Anita1, Krishna Gautam2 , J.S. Kushwaha3 , Brijesh Kumar4, Dharmender5


12 © JIMI • AUG. - OCT. 2018 • VOL. 12

infections. When both HIV and HBV co-infect a patient, the mortality rate from chronic hepatitis B is increased over and above that of either infection alone with a more speedy progression of liver fibrosis and an elevated rate of cirrhosis decompensation2.The prevalence of hepatitis B in HIV infected individuals has been reported to be higher than that in the general population. With a more rapid progression of liver disease in HIV patients with hepatitis B, HBV has become an important cause of liver-related morbidity and mortality in these patients. As a result, emphasis has been given on the diagnosis of HBV in the management of HIV infected patients.Hepatitis B is a major public health problem in Indian subcontinent where the average carrier rates in the general population are estimated to be about 4%. Saravanan S et al10 from South India studied a total of 500 HIV positive patients and reported that HBV co-infection was detected in 45/500 (9%) patients.Padampriyadarshini et al3 from South India reported that out of the 951 HIV-infected patients, 61 patients (6.4%) were HBsAg positive. In addition, the rate of HBV co-infection in HIV patients have been reported variably depending on the risk group, type of exposure involved and the geographic region of the patients studied. The literature regarding the prevalence of HIV co-infection with HBV in India is scarce. Hence, this study was done to see the prevalence of co-infection of HBV among HIV infected subjects.Materials and methods:This hospital-based cross-sectional study was conducted at LLR and Associated Hospitals, and ART plus centre, GSVM Medical College, Kanpur (UP) from April 2017 to September 2018 in which a total of 300 adult male and female HIV seropositive patients of 18 years and above were enrolled in the study.Study period: From April 2017 to September 2018. Place of study: LLR and Associated Hospitals and ART plus centre, GSVM Medical College, Kanpur (UP).Design of the study: Hospital-based cross-sectional study conducted on adult HIV seropositive patients.Inclusion criteria: All adult male and female HIV seropositive patients of 18 years and above.Exclusion criteria:• HIV negative patients• Patients not giving consent for the study

Eligible patients were included in the study after counselling about the study, its nature, and relevance. All the patients were interviewed and clinically examined along with the recording of demographic variables. Informed consent was obtained from all subjects and patient’s confidentiality was maintained. Ethical clearance was obtained from the ethics committee, GSVM Medical College, Kanpur (UP).Investigations: 1. HIV testing as per NACO guidelines 2. ELISA for HBsAg Statistical analysis: The data was analyzed using SPSS version 13. The data was presented by the mean and standard deviation (SD) for continuous variables and by the frequency with their respective percentages for categorical variables. Chi-square test was used to test the association between categorical variables. A p value of <0.05 was considered as statistically significant.Results: Serum samples from a total of 300 HIV-positive patients were tested in this study. The demographic data of these patients were recorded. Out of 300 patients, 195 (65 %) were males and 105 (35 %) females. The majority of the HIV-infected patients were in the 21-50 years age group. Mean age of the HIV positive patients was 36.49+/- 8.69 years (95% CI) (Table 1).

TABLE 1 AGE WISE DISTRIBUTION OF CASES

Age (Years) No. of Cases Percentage (%)<21 00 0

21-30 99 3331-40 102 3441-50 99 33>50 00 00

Total Cases 300 100TABLE 2 AGE WISE DISTRIBUTION OF HBsAg CO-INFECTED PATIENTS

Age Group (Years)

ELISA for HBsAg Total CasesReactive Non Reactive

<21 00 00 0021-30 33 66 9931-40 00 102 10241-50 00 99 99>50 00 00 00

Total Cases

33 267 300

Mean age of the HIV-HBV co-infected patients was 28.36+/- 1.51 years (95% CI) and all HIV-HBV co-


13© JIMI • AUG. - OCT. 2018 • VOL. 12

infected patients were seen in the 21-30 year age group (100%) ( Table 2).TABLE 3 GENDER WISE DISTRIBUTIONS OF HBsAg CO-INFECTED PATIENTS

Sex ELISA for HBsAg Total Cases

Reactive Non-reactiveMale 18 177 195

Female 15 90 105Total Cases

33 267 300

The rate of HBsAg co-infection was 11% (33/300) in HIV positive patients. Among males, HIV/HBV co-infection was seen in 18 out of 195 (9.2 %) patients. Among the females, HIV/HBV co-infection was seen in 15 out of 105 (14.2 %) patients (Table 3).DiscussionAmong the HIV infected patients worldwide, 2 to 4 millions are estimated to have chronic HBV co-infection4. A large number of people are living with HIV in India too. Co-infection of HIV with HBV may adversely affect the clinical course, management and the therapy for HIV infection. Approximately two-thirds of patients with AIDS develop abnormalities in liver function tests5. Liver dysfunction may be directly related to HIV infection or may result from conditions such as intravenous drug abuse, alcoholism or prior viral hepatitis, which are more prevalent in patients with HIV infection. In addition, sepsis, malnutrition or the administration of possibly hepatotoxic antiretroviral medications may also lead to liver dysfunction6,7.The survival rates of HIV patients have increased due to decrease in opportunistic infections as a consequence of highly active antiretroviral therapy (HAART). As a result, the focus has shifted to the management of concurrent illnesses like chronic HBV infection having a potential to increase long-term morbidity and mortality. Due to the similar risk factors and the transmission routes, HIV patients have an increased risk of HBV infection as compared to those uninfected with HIV.The reported co-infection rates of HBV in HIV patients have been variable worldwide depending on the risk group, type of exposure involved and geographic region. In India, HBV co-infection among HIV infected patients has been reported infrequently from region to region.Gupta et al8 analyzed serum samples from 451 HIV positive patients for HBsAg and HCV antibodies during a period of three years (Jan 2003 to Dec 2005) at a tertiary

care hospital in New Delhi, India. The prevalence rate of HBsAg in this population was 5.3% as compared to 1.4% in apparently healthy donors (p < 0.001). Another study was done by Tripathi et al9 at a referral hospital in North India. A total of 620 HIV positive patients were studied. HBV co-infection was detected in 2.25%.A study was done at AIIMS, New Delhi India for a period of 6 years between January 2002 to December 2007, 837 HIV positive patients (631 males and 206 females, M:F:: 3:1) were enrolled in the study. Amongst them, 7.28 % of HIV positive patients showed the presence of HBsAg as compared to 1.4 % in HIV negative control group.Our study findings indicate that HIV-infected men and women are an increased risk of viral co-infections as illustrated by the high prevalence of HBsAg (11%). HIV-HBV co-infection was comparable in both males and females (18 vs 15).Our findings show that the prevalence of co-infection for HIV and HBV was highest in the 21-30 years age-group, which is the normal age group where the HIV infection is reportedly higher as per Indian literature. This also suggests that sexual route could also be the common route of transmission for both HIV and HBV.In the present study, the seroprevalence of Hepatitis B was 11% which is similar to the prevalence reported by Saravanan S et al10 (9%) but higher than that reported by Tripathi et al9 (2.25%) and Gupta et al8 (5.3%).

ConclusionIn our study, the prevalence of Hepatitis B virus co-infection in HIV positive patients is found to be 11 %. This is significantly higher as compared to the prevalence of Hepatitis B virus infection in the general population of this region.The presence of HBV co-infection in HIV patients is challenging to the Indian economy as currently there is an increase in the number of patients diagnosed with HIV disease. The knowledge of co-infection in an HIV positive patient is of considerable importance since these patients, as they have a longer life-expectancy on antiretroviral treatment will also require management for their co-infection with HBV. Therefore, screening for hepatitis B virus infection in all HIV positive patients should be made a routine protocol in all developing countries including India. Limitation of study: The present study has certain limitations. Firstly, this is a cross-sectional study unable to adequately establish a causal relationship between the time of exposure and subsequent infection. Secondly, the


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study was conducted with patients limited to a tertiary hospital setting and not community setting. However, the results can be considered to approximate for clinical care of our HIV-infected patients. Moreover, the HIV negative group was not enrolled.

References: 1. National AIDS Control Organization (NACO). HIV/

AIDS epidemiological Surveillance & Estimation report for the year 2017. Available from: http: //www.nacoonline.org/

2. Puoti M, Torti C, Bruno R, Filice G, Carosi G. Natural history of chronic hepatitis B in co-infected patients. J Hepatol. 2006;44: S65–70.

3. Padmapriyadarsini C, Chandrabose J, Victor L, Hanna LE, Arunkumar N, Swaminathan S. Hepatitis B or hepatitis C co-infection in individuals infected with human immunodeficiency virus and the effect of anti-tuberculosis drugs on liver function. J Postgrad Med. 2006;52:92-96.

4. Alter M. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44(Suppl 1): S6–9.

5. Sud A, Singh J, Dhiman RK, Wanchu A, Singh S, Chawla Y. Hepatitis B virus co-infection in HIV infected patients. Trop Gastroenterol. 2001; 22:90-92.

6. Kumarasamy N, Solomon S, Flanigan TP, Hemalatha R, Thyagarajan SP, Mayer KH. Natural history of human immunodeficiency virus disease in southern India. Clin Infect Dis. 2003;36:79-85.

7. Bhattacharya S, Badrinath S, Hamide A, Sujatha S. Co-infection with hepatitis C virus and human immunodeficiency virus among patients with sexually transmitted diseases in Pondicherry, South India. Indian J Pathol Microbiol. 2003;46:495-97.

8. Gupta S, Singh S. Hepatitis B and C virus co-infection in Human Immunodeficiency virus positive North India patients. World j Gastroenterol. 2006;12: 6879-83.

9. Tripathi AK, Khanna M, Gupta N, Chandra M. Low prevalence of Hepatitis B virus and Hepatitis C virus co-infection in patients with Human Immunodeficiency Virus in Northern India. J Asso Physio Ind. 2007;55: 429-31.

10. Saravanan S, Velu V, Kumarasamy N, Nandakumar S, Murugavel KG, Balakrishnan P, et al. Co-infection of Hepatitis B and Hepatitis C virus in HIV infected patients in South India. World J Gastroenterol. 2007;7:5015-20.


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AbstractThe present study intended to determine the diagnostic value CSF CRP/glucose/cell count in identification of the causative organism. It was conducted at large tertiary care hospital where all enrolled patients presenting with signs of CNS infection were subjected to CSF examination for protein, cell count, glucose level, CRP level and. We found that tuberculosis was most common etiology followed by pyogenic and viral meningitis; fever was most common symptoms followed by headache and vomiting. CSF protein positively correlated with CSF CRP levels, ratio of CSF to blood glucose negatively correlated with CSF CRP level, CSF CRP level was statistically higher in pyogenic meningitis.Evaluation of CNS infection by cost effective measures like CSF CRP/ cell count and protein levels can help in early identification of causative organism and early initiation of antibiotics thus minimizing mortality and sequelae.

Assessment of CSF CRP/Protein/Glucose to Determine EtiologicalAgent in CNS Infections

Original Article

In such circumstances the determination of CSF CRP and CSF ADA appers to provide a new dimension to specific diagnois of meningitis. C reactive protein is an acute phase reactant of “Pentaxin” group of family, discovered in 1930 by Tillet et al 1. Increased serum CRP levels signify acute phase response, thus increase CSF CRP signifies meningeal involvement CSF CRP testing appear to be an attractive option for rapid diagnosis of pyogenic meningitis and hence many studies have been done to evaluate this role of CSF CRP. CRP is an abnormal serum glycoprotein produced by the liver during acute inflammation. Because it disappears rapidly when inflammation subsides, its detection signifies the presence of a current inflammatory process. CRP production is a non-specific response to disease and it can never, on its own, be used as a diagnostic test. However if the CRP result is interpreted in the light of full clinical information of the patient then it can provide exceptionally useful information. Synthesis of CRP and other acute phase proteins by hepatocytes is modulated by cytokines. Interleukins 1b and 6 and tumour necrosis factor are the most important regulators of CRP synthesis. CSF CRP concentrations are sevenfold lower than those of serum2. This difference is explained by direct hepatic release of CRP into plasma, which then undergoes ultrafiltration to form CSF. Meningeal irritation stimulates CRP production. Once CRP enters the CSF it binds to damaged tissue.

Thus, the present study was designed to evaluate the diagnostic utility of CSF CRP/glucose and cell count levels in clinically diagnosed cases of meningitis.

Ram Avatance Sharma1, M.L. Pursnani2, Ravindra Singh Chahar3, Nikhil Pursnani4, Prabhat Agrawal5, Ashish Gautam6

IntroductionCNS infection are among the major cause of morbidity & mortality. To decrease the incidence, it is mandatory that they are diagnosed early & treated promptly. The therapeutic outcome in meningitis is directly proportional to the time of starting the specific therapy “The dictum is treatment delayed is treatment denied”. The etiological diagnosis of meningitis remains a problem in clinical practice as CSF biochemical analysis and cellular response often overlap. Thus, there is a need of rapid and etiological diagnosis of meningitis for better clinical outcome.

Test like PCR and ELISA are although helpful but are costly, not easily available, and also not easily performed.

1. Assistant Professor, Dept. of Medicine, F.H Medical college, Tundla, Agra

2. Professor, Dept. of Medicine, F.H. Medical college, Tundla,Agra

3. Senior consultant physician, Dept. of Cardiology, S.N. Medical college and hospital, Agra (Corresponding Author)

4, 5, 6. Assistant Professor, Dept. of Medicine, S.N. Medical college, Agra E-mail: [email protected]


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Material and MethodsA total of 100 patients of suspected meningitis admitted in department of Medicine and neurology S N Medical College Agra and F H medical college Agra during Dec 2017 to June 2018 were taken for study.

Subjects more the 18 years and satisfying the clinical criteria of meningitis were included for the study. Exclusion criteria includes, 1) Patients less than 18 years, 2) patients with acute infections at sites other than the central nervous system, 3) Patient in whom lumbar puncture was contraindicated, 4) Patient with severe hepatic dysfunction or severe dyslipidemia and 5) subjects using Steroid.

All the patients were taken for study were subjected to complete history, clinical examination, relevant laboratory investigation including total & differential leucocyte count, x-ray chest, fundus & CT head. CSF examination was conducted by lumbar puncture and samples were analysed for total prfotein, cell count, differential cell count, and CRP levels. Informed consent was taken for all procedure conducted in this study.

ResultsTubercular was most common etiology followed by pyogenic and viral meningitis table 1. Fever (95%) was the most common complaint followed by headache (83%). Other complaints were vomiting (52%), altered sensorium (45%) seizures (16%), drowsiness (8%), focal neurological deficits (9%), stupor (5%) and coma (4%). (Table 2)

Table No. 1 Distribution of the type of meningitis

Type of meningitis Number %TBM 49 49Pyogenic Meningitis 30 30Viral Meningitis 21 21Total 100 100

49% Patients had TBM, 30% had Pyogenic Meningitis, 21% had Viral Meningitis.

Table No. 2 Clinical Presentation of Meningitis

Clinical Presentation Number %Fever 95 95Headache 83 83Vomiting 52 52Seizures 16 16Focal Neurological deficits

09 09

Altered sensorium 45 45Drowsiness 08 08Stupor 05 05Comatose 04 04

Table No. 3 Relation between CSF Cell count with CSF CRP in Pyogenic Meningitis

CSF cell Count

No. of Count

CSF CRP (mg/dl)Mean SD

<300 7 12.58 ±2.230

301-600 12 16.29 ±2.84

>600 11 26.15 ±3.99

Table No. 4 Relation between CSF Protein with CSF CRP in Pyogenic Meningitis

CSF Protein No. of Count

CSF CRP (mg/dl)

Mean SD

<100 11 14.2 ±3.766

101-200 13 19.707 ±6.22

>200 6 26.46 ±4.19

Table No. 5 Relation between CSF Glucose/blood glucose with CSF CRP in Pyogenic Meningitis

CSF Glucose/blood glucose

No. of Count

CSF CRP (mg/dl)

Mean SD

<0.4 9 14.71 ±7.006

0.2-0.4 13 17.93 ±4.33

<0.2 8 25.7 ±4.33

Table no. 6 P value of CSF CRP

Type of men-ingitis

Total no. cases

CSF CRP (.8mg/dl)

No. (%) P value

TBM 49 0

Pyogenic meningitis

30 28 < 0.0001

Viral meningitis

21 0


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The CSF CRP cutoff level was taken as > 5mg/dl, 28 out of 30 patients of pyogenic meningitis had CSF CRP level > 8mg/dl which was statistically significant.

Increased CSF protein correlated positively with increased CSF CRFP levels (Table 4). In this group suggest that those with higher protein levels have higher CRP levels. This different was found to be statistically significant (p < 0.0001). This was also the finding in the studies of Goran rajs et al (2002)3 , Park JW et al (2003)4 & Lindquist et al (2005)5.

The mean CSF CRP levels were calculated & it was evident that the ratio of CSF to blood glucose increased, the mean levels of CSF CRP decreased. The study population was divided into 3 group with CSF to blood glucose ratio being < 0.4, 0.2-0.4 and < 0.4, and the difference between mean CRP of these group was found to be statistically significant ( p< 0.001) (Table 5 and 6).

Goran Rajs et al, have observed that CSF-CRP levels are higher in gram- negative pyogenic meningitis compared to gram positive Pyogenic meningitis suggesting that infection with gram-negative bacteria probably enhances permeability of CRP through the blood brain barrier.7 A recent meta-analysis by Gerdes LU at al suggested that a negative CRP test in either CSF or serum can be used with a very high probability to rule out bacterial meningitis6.

Riberio MH et al estimated the levels of CRP in CSF from 33 patients with Bacterial meningitis, 21 patients with lymphocytic meningitis and 54 controls7. 100% of these patients with bacterial meningitis were currently classified on the basis of measurement of CRP levels in CSF. No more than 4% of patients were incorrectly classified as belonging to the bacterial group on the basis of CRP levels in CSF. In conclusion authors recommend the estimation of CRP in CSP in the differentiation of bacterial form non-bacterial meningitis.10

Hemavani V at al evaluated the role of CRP in CSF in differentiation of meningitis. The study included 499 CSF samples from cases of viral, pyogenic, tuberculous and fungal meningitis and 580 normal CSF samples. CRP positive by qualitative latex agglutination test was seen in 73.3% of samples from partially treated pyogenic meningitis and 92% among meningitis cases. All suspected cases of tubercular meningitis were negative for CRP in the CSF while only 1 out of CSF samples for bacteriologically confirmed tuberculous meningitis was positive. CRP was raised in 27.2% and 12.5% of CSF sample from candida

and cryptococcal meningitis respectively. While none of the 102 samples from suspected viral meningitis and 580 non-meningitis cases were positive for CRP in the CSF. The study concludes that CSF CRP determination can be of value to differentiate pyogenic versus other microbial meningitis etiology. However, it cannot differentiate between tuberculosis, fungal and viral meningitis8,9.

In study by Tankhiwale SS et al 31 out of 75 cases (46.66%) were positive for CSF-CRP while 34 were positive for only serum CRP. Thus, total of 66 patients showed raised CRP levels in either in serum or CRP while only 27 yielded bacterial growth in culture. The difference was statistically significant. Hence, the authors concluded that estimation of CRP in CSF and serum help as an early marker for repid diagnosis of pyogenic meningitis.10

Similar results were seen after reviewing previous studies and standard test available on the matter11,12,13,14. In our study, CSF CRP level did not bear any correlation with clinical presentation & outcomes in pyogenic meningitis.

ConclusionCSF CRP level was found to be higher in patients of pyogenic meningitis when compared to TBM and viral meningitis. CSF CRP level Correlation with CSF count, CSF protein & CSF to blood glucose ratio, but there was no correlation between CSF CRP level with clinical presentation and mortality in pyogenic meningitis. Using cut off >0.4 mg/dl for CSF CRP, the sensitivity and specificity of CSF CRP for diagnosis of pyogenic meningitis was found to be 93.33% and 100% respectively.

References: 1. Tillett, W.S. and francis, T. Jr.: Serological reactions

in pneumonia with a non-protein somatic fraction of pneumococcus, J. Exper. Med., 52:561-571,1980.

2. PepysMB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111:1805-12.

3. Goran Rajs, Zvezdana Finzi-Yeheskel, Andrea Rajs and Michael Mayer. C-Reactive Protein Concentrations in Cerebral Spinal Fluid in Gram-positive and Gram-negative Bacterial Meningitis.2002. Clinical Chemistry 48: 591-592.

4. Park JW, Chung SW, Ko SB, Choi YB, Lee KS. Predictive Value of C-Reactive Protein in the Differential Diagnosis of Acute Meningitis in Adults. Korean Neurol Assoc.2003 Jun;21(3):248-254.


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5. L. Lindquist, T. Linne, L.O. Hansson, M. Kalin and G. Axlesson. Value of Cerebrospinal fluid andlysis in the differential diagnosis of meningitis: A study in 710 patients with suspected central nervous system infection. European Journal of Clinical Microbiology & Infectious Diseases. 1988 June; 7(3):374-380.

6. Rifai N, Warnick RG. Teitz Textbook Of Clinical Chemistry & Molecular Diagnostics. 4th ed: Butterworth Heinemann: 1999:962-3.

7. Ribeiro MA, Kimura RT, Irulegui. Cerebrospinal Fluid levels of lysozyme, IgM and C-reactive protein in the identification of bacterial meningitis. J Trop Med Hyg 1992;95(2):87-94.

8. Hemavani N, Chitnis D, Joshi SP. C-Reactive protein in CSF and its role in Differential diagnosis of meningitis. Ind J Med Microb. 2001; 19(1):26-9.

9. B. Talukdar et al. Meningocococal meningitis- Clinical observation during an epidemic. Ind. Ped. 1988;25(4):310-312.

10. Tankhiwale SS, Jagtap PM, Khadse RK, Jalgaonkar SV. Bacteriological study of pyogenic meningitis with

special reference to C-reative protein. Indian Journal of Medical Microbiology.2001;19(3):159-160.

11. Gambhir IS, Mehta M, Singh DS, Khanna HD. Evaluation of CSF- Adenosine deaminase acticity in tubercular meningitis. JAPI 1999;47(1):192-4.

12. Rooijen VM, Hansson LO, Forstegrad J, Silaveira A, HAmsten, Bremme K. Treatment With Combined oral Contraceptives induces a reise in serum C-reactive protein in the absence of a general inflammatory reponse. J Thromb Haemost. 2006 Jan;4(1) 77-82.

13. Sutinen J, Sombrero L, Paladin FJ. Etiology of Central Nervous system infection in the Philippines and the role serum C- reactive protein in excluding acute bacterial meningitis. Int J Infect Dis 1998;3(2):88-93.

14. Ray P, Badarou-Acossi G, Viallon A, Boutoille D. Accuracy of Cerebrospinal fluid results to differentiate bacterial form non-bacterial meningitis, in case of negative gram stained smear. Am J Emerg Med. 2007 Feb; 52(2): 179-84.


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AbstractIntroduction: A few studies have reported an increased prevalence of fibromyalgia in diabetes. Also, an association of hypomagnesemia with diabetes mellitus as well as neuromuscular symptoms, muscle pains and cramps has been reported.

Aim: To determine the prevalence of fibromyalgia in type 2 diabetes mellitus and its association with serum magnesium levels.

Material and methods: In our case-control study, cases included patients of Type 2 Diabetes and controls comprised of age and sex matched, healthy non-diabetic individuals. All patients with chronic wide-spread pain were evaluated for the presence of fibromyalgia. Serum magnesium levels were measured in patients with fibromyalgia and in those with chronic widespread pain not fulfilling the criteria for fibromyalgia.

Results: Prevalence of fibromyalgia in cases was 11% as compared to 3% in controls(p=0.027). Mean fasting blood sugars, 2h-post prandial blood sugar and HbA1C among diabetics with and without fibromyalgia were 198.9± 99.8mg/dl and 131.7± 45.6mg/dl (p<0.001); 322.6± 113.3mg/dl and 209.7± 54.6mg/dl(p<0.001); and 8.91± 1.21% and 7.30± 0.73%(p<0.001), respectively. Prevalence of hypomagnesemia in cases with fibromyalgia was 63.6% as compared to 7.1% in diabetics without fibromyalgia (p<0.001). There was a weak inverse correlation between serum magnesium levels and number of tender points involved(r=-0.359; p=0.010).

Conclusion: There is an increased prevalence of fibromyalgia among diabetics, especially those with poor glycemic control and longer duration of diabetes. Hypomagnesemia is significantly more prevalent in patients with fibromyalgia than in those with similar symptoms who do not fulfil the diagnostic criteria.

Fibromyalgia Linked to Uncontrolled Diabetes Mellitus and Hypomagnesemia

Original Article

Human Immunodeficiency Virus, Lyme’s disease and Hepatitis C virus[4,5]. Although many rheumatological disorders have been described in patients with diabetes, the literature on its association with fibromyalgia is limited. A few small studies have pointed to an increased prevalence of fibromyalgia in diabetes with a positive correlation between higher levels of HbA1c and number of tender points [6]. Also, the etiopathogenesis of fibromyalgia still remains unidentified. Low red blood cell magnesium levels and the consequent abnormal metabolism of vitamin B1 has been proposed as a possible etiopathological mechanism [7]. The association of diabetes with lower magnesium levels has also been shown in some studies[8]. In the present study we have attempted to assess the prevalence of fibromyalgia among patients with diabetes mellitus and determine its association with serum magnesium levels.

J. Fatima1, V. Jain2, S. Priya3, R. Karoli4, V. Shukla5, Z. Siddiqi6, KI Khursheed 7, A. Kumar8

1. Professor, ELMC&H, Lucknow2. Assistant Professor, ELMC&H, Lucknow

(Corresponding Author) E-mail: [email protected]

3, 4. Assistant Professor, ELMC&H, Lucknow5, 6, 7, 8. Junior Resident, ELMC&H, Lucknow

IntroductionFibromyalgia is a disorder with cardinal symptoms of diffuse chronic pain with muscle stiffness and tenderness at specific points on examination with an estimated prevalence ranging between 0.5% and 3.4%[1]. It is more common in females with a female-to-male ratio of 9:1.Incidence of fibromyalgia is found to be higher in patients with Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Sjogren’s syndrome (SS), Osteoarthritis[2,3]and infections like


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AimTo determine the prevalence of fibromyalgia in type 2 diabetes mellitus and its association with serum magnesium levels.

Materials and MethodOurs is a Case-Control Study conducted in the Department of Medicine at a tertiary care referral centre in Lucknow from January 2014 to June 2015. The study was done on 2 groups- Cases included patients of Type 2 Diabetes (ADA 2013 criteria) and Controls comprised of age and sex matched, healthy non Diabetic individuals. Fasting blood sugar, 2h postprandial blood sugar and HbA1C were done in all participants.All individuals with known joint disease, acute febrile illness,and acute metabolic complications of diabetes or renal dysfunction were excluded from the study.

The approval for the study was obtained from Institute’s Ethical Committee. An informed written consent was obtained from all the study participants.

Study participants who had chronic widespread aches and pains (from either group) were assessed for presence of fibromyalgia.

Serum magnesium was assessed in all of the patients who were having fibromyalgia syndrome in both study and control groups.Additionally, serum magnesium levels were also evaluatedin those patients who were having symptoms suggestive of fibromyalgia but did not fulfil thecriteria.

The first part of the study was targeted to see the difference in prevalence of fibromyalgia between cases and controls and the second part to determine the association of fibromyalgia with serum magnesium levels.

Definitions:

Overweight:Body Mass Index (BMI) -23-24.9 kg/m2 (WHO criteria)

Obese: BMI>24.9 kg/m2

Fibromyalgia was diagnosed according to the 1990 ACR criteria[9]:

• Widespread body pain

– Pain on both left and right sides of the body

– Pain above and below the waist

– Axial pain present

• Pain persisting ≥3 months

• Pain in ≥11 of 18 tender points on digital palpation. Palpation should be done to produce approximately 4 kg pressure, which is the degree of force required to just blanch the examiner’s thumbnail. Palpation should be perceived as painful and not tender to be considered positive. Nine pairs(18) of tender points defined are as follows

Occiput: bilateral, at the suboccipital muscle insertions.

Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5-C7.

Trapezius: bilateral, at the midpoint of the upper border.

Supraspinatus: bilateral, at origins, above the scapula spine near the medial border.

Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces.

Lateral epicondyle: bilateral, 2 cm distal to the epicondyles.

Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle.

Greater trochanter: bilateral, posterior to the trochanteric prominence.

Knee: bilateral, at the medial fat pad proximal to the joint line.

Diabetes Mellitus was diagnosed on the basis of ADA 2013 criteria. [10]

Serum Magnesium levels were measured using VITROS dry Chemistry. Serum Magnesium levels 1.3-2.5meq/l were considered normal. Hypomagnesemia was defined as serum magnesium levels <1.3meq/l.[11]

STATISTICAL ANALYSIS

The data obtained was subjected to statistical analysis using Statistical Package for Social Sciences version 15.0. Data was represented as numbers and percentages. Parametric data was presented as mean±SD.

Chi-square test was used to evaluate the proportional data. Odds ratio/risk ratios have been calculated wherever necessary. Parametric data has been evaluated using Student “t”-test.

Confidence level of the study was kept at 95%, hence a “p” value less than 0.05 indicated a statistically significant difference.


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Results

A total of 200 subjects were enrolled in the study which included 100 confirmed cases of diabetes mellitus from Diabetes Clinic and 100 age and gender matched controls.

Age of subjects ranged from 27 to 76 years. Baseline

characteristics and baseline hematological and biochemical parameters of the two groups are shown in table 1. There was significant difference in BMI and glycemic control indices between cases and controls (p<0.001). The rest of the parameters were comparable between 2 groups.

Baseline characteristics Cases (n=100) Controls (n=100) P valueAge in years 54.04±9.77 52.98±10.22 0.420Percentage of males(%) 45 41 0.568Percentage of patients with BMI ≥ 25Kg/m2(%) 38 11 <0.001*Fasting blood sugar (mg/dl) 139.1±57.5 71.3 ± 11.4 <0.001*Post prandial blood sugar (mg/dl) 222.1±72.1 114.4 ± 28.2 <0.001*HbA1c (%) 7.48±0.93 5.02 ± 0.98 <0.001*S. Calcium 8.1±0.32 8.3±0.74 0.110S. Uric acid 5.34±1.06 4.88±0.92 0.156S. Creatinine 1.28±0.57 1.04±0.22 0.139S. Magnesium 1.99±0.75(n=39) 1.88±0.43(n=11) 0.635Table 1: Baseline characteristics and lab data of Cases and Controls. All values are Mean ± SD, unless mentioned otherwise. Significance of difference between the two groups was calculated using student-t test.* = Significant difference.

Fibromyalgia syndrome Cases (n=100) Controls (n=100)Present[Number(%)] 11 (11) 3 (3)Absent[Number(%)] 89 (89) 97 (97)Mean No. of tender points involved±SD (Range) 2.81±4.10 (0-14) 0.86±2.62 (0-14)Table 2: Prevalence of fibromyalgia and mean number of tender points involved among cases and con-trols. x2 = 4.916; p=0.027

There was a significant difference between the prevalence of fibromyalgia between the 2 groupswith fibromyalgia being present in 11% of cases as compared to only 3% controls (p=0.027)(table 2). The demographic and anthropometric characteristics were similar among cases with and without fibromyalgia(Table 3).

Comparison of glycemic control between diabetic patients with and without fibromyalgia is shown in table 4. Among the cases glycemic control was poorer among patients with fibromyalgia. Also, majority of the patients with fibromyalgia had been diabetic for more than 5 years [9 out of 11(81.8%)]. On the other hand, most of the patients without fibromyalgia had been diabetic for 5years or less [77 out of 89(86.5%)].

Characteristics No fibromyalgia (n=89) Fibromyalgia (n=11) Significance of differenceMean ± SD Mean ± SD “t” “p”

Age (yrs) 53.70± 9.64 56.82± 10.81 1.000 0.320BMI (kg/m2) 24.42± 2.81 24.82± 4.25 0.417 0.678Male: Female[n(%)] 43 (48.3%): 46 (51.7%) 2 (18.2%): 9 (81.8%) x2=3.592; p=0.058Table 3: Demographic and anthropometric characteristics of diabetic patients with and without fibromyalgia.


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Serum Magnesium levels were done in only 39 patients which included 11 fibromyalgia patients and 28 patients who had similar symptoms but did not fulfil the tender point criteria. Mean values were 2.11±0.62meq/l and 1.70±0.99meq/l in the 2 groups, respectively. The difference was not statistically significant(p=0.123).However, hypomagnesemia(S. Mg < 1.3meq/l) was significantly more prevalent in diabetics with fibromyalgia (Table 5).

Parameter No fibromyalgia(n=89)

Fibromyalgia (n=11)

Significance of difference“t” “p”

Fasting blood sugar (mg/dl) 131.7± 45.6 198.9± 99.8 3.915 <0.001Post prandial blood sugar (mg/dl) 209.7± 54.6 322.6± 113.3 5.594 <0.001HbA1c (%) 7.30± 0.73 8.91± 1.21 6.362 <0.001Table 4: Comparison of glycemic control among diabetic patients with(n=11) and without(n=89) fi-bromyalgia. All values are mentioned in Mean ± SD. P<0.05 is considered statistically significant.

S. Magnesium levels (meq/l) Symptomatically similar patients not fulfilling tender points criteria (n=28)

Fibromyalgia (n=11)

No. % No. %Below normal (1.3 meq/l) 2 7.1 7 63.6Normal (1.3-2.5 meq/l) 18 64.3 1 9.1Above normal (>2.5 meq/l) 8 28.6 3 27.3Table 5: Distribution of subjects with diabetes according to the serum magnesium levels and presence or absence of fibromyalgia. x2=15.675 (df=2); p<0.001

There was a weak, though statistically significant inverse correlation between serum magnesium levels and the number of tender point involved (Figure 1)

Figure 1: Correlation between serum magnesium levels and number of tender points involved. (r=-0.359; p=0.010).


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DiscussionFibromyalgia syndrome (FMS) is an under-diagnosed disorder of unknown etiology, characterized by chronic widespread muscular pain, often accompanied by somatic and psychological symptoms.In spite of some scepticism, ithas been accepted as a valid, unique clinical diagnosis and the main theory explaining it may relate to many chronic pain states [12]. Autonomic dysregulation alongwith neuroplasticity leading to abnormal connections between sympathetic nervous system and nociceptive fibres leading to neuropathic pain has been proposed as one of the pathophysiological mechanisms leading to fibromyalgia[13]. Autonomic neuropathy is also common in diabetes mellitus presenting with various gastrointestinal, genitourinary and cardiovascular symptoms, with hypoglycemia unawareness and silent myocardial infarctions being some of its serious manifestations [14]. Thus, autonomic neuropathy being a consequence of poor glycemic control on one hand and an etiopathological factor for fibromyalgia on the other - it is likely that prevalence of fibromyalgia would be more in patients with diabetes. This may be further supported by the fact that prevalence of musculoskeletal disorders in diabetes is higher as compared to the general population.[15,16,17]According to our study Fibromyalgia and diabetes occur together nearly four times more often than non-diabetic controls.In the present study, 38% of cases with diabetes were overweight or obese. Despite our best efforts the matching by weight could not be done between case group and control group as it was difficult to find out overweight and obese subjects with a normal health status. Moreover, obesity is an important risk factor for insulin resistance and diabetes.[18,19]These observations are in accordance with the a study by Tishler et al.(2003), where higher prevalence of fibromyalgia was found in type 1 and type 2 diabetes mellitus as compared to normal populationwith a prevalence of 15.5% in type 2 diabetes mellitus as compared to 2% in controls[6]. Worldwide prevalence of fibromyalgia varied from 0.2 to 4.7%, however maximum prevalence of 6.4% was found in one of the regions of United States when the modified ACR criteria of 2010 was used for diagnosis.[20,21] Relatively lower prevalence of fibromyalgia in our study may be attributed to a relatively lower prevalence of fibromyalgia in general in India, although the data is quite limited.[22]

We also observed that diabetes control was poorer and DM duration longer in patients with fibromyalgia. This probably can be explained by greater neuronal damage with poorer diabetes control and also progressive neuronal injury due to prolonged uncontrolled diabetes.There was a significant association of fibromyalgia with poor diabetes control (as reflected by higher fasting blood glucose and HbA1c level). An association between higher HbA1c levels and fibromyalgia has been reported.[6,23] Nerve injuries are more likely to occur with poor glycemic control and eventually result in diabetic neuropathy. [24]This might contribute to fibromyalgia as similar pathophysiology of neuropathic pain and fibromyalgia has been proposed recently.[25]Serum magnesium levels were done only in patients with fibromyalgia or in those with similar symptoms but not fulfilling the tender point criteria. Serum magnesium levels in diabetes have been reported to be altered as compared to healthy controls. [8]When studying the relationship between fibromyalgia and serum magnesium we found that hypomagnesemia, i.e., serum magnesium less than 1.3meq/l was significantly more in patients with fibromyalgia. Our study showed a mild inverse correlation between serum magnesium levels and number of tender points involved among diabetic subjects (r=-0.359; p=0.010). Serum magnesium levels were not evaluated in all the study subjects. Earlier studies have shown an association ofmagnesium deficiency with muscular pain and cramps.[26] By including symptomatically similar patients only, the association between fibromyalgia and hypomagnesemia could be better established.Association of trace elements such as selenium and magnesium with fibromyalgia are being explored since a long time.[7, 27, 28]Fibromyalgia patients were found to have low red blood cell magnesium levels. These low magnesium status were in turn linked to abnormal metabolism of vitamin B1 which subsequently was proposed as one of the etiopathological mechanisms of fibromyalgia.[7]

Wolfe et al. (2010)has proposed a new criteria for diagnosis of fibromyalgia. [29] This criteria focused on wide spread pain index rather than tender point count. The advantage of the criteria is that it is practical and can be used by a primary care physician.[30] Using the tender point criteria by an untrained primary care physician leads to erroneous or incomplete assessment and hence misdiagnosis. This problem is overcome with the new


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criteria. However, we used the 1990 ACR criteria as it was mainly developed for research purposes and most of the studies on fibromyalgia have used this criteria, thus making comparison easier.[31] However, combining the 2 criteria would have increased the diagnostic accuracy.[31]

ConclusionDespite its limitations, the present study was able to establishan increased prevalence of fibromyalgia among diabetics, especially those with poor glycemic control and longer duration of diabetes. Also, hypomagnesemia was found to be significantly more in patients with fibromyalgia than in those who had similar symptoms but did not fulfil the criteria.

The associations elucidated in the present study hold relevance, yet much has to be done in establishinga relationship of fibromyalgia with other co-morbidities.This study lays stress on the importance of checking serum magnesium levels in patients with diabetes mellitus and fibromyalgia. It also suggests correction of hypomagnesemia as a potential treatment for fibromyalgia. Further research on this aspect might add to our limited knowledge on this important yet ignored subject.

References:1. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L.

The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995 Jan;38(1):19-28.

2. Middleton GD, McFarlin JE, Lipsky PE. The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum. 1994;37(8):1181-1188.

3. Wolfe F, Petri M, Alarcón GS, et al. Fibromyalgia, Systemic Lupus erythematosus (SLE), and evaluation of SLE activity. J Rheumatol. 2008;36(1):82-88.

4. Thompson ME, Barkhuizen A. Fibromyalgia, Hepatitis C Infection, and the Cytokine Connection. Current Pain and Headache Reports 2003, 7:342–347

5. Cassisi G, Sarzi-Puttini P, Cazzola M. Chronic widespread pain and fibromyalgia: could there be some relationships with infections and vaccinations? Clin Exp Rheumatol. 2011 Nov-Dec;29(6 Suppl 69):S118-26.

6. Tishler M, Smorodin T, Vazina-Amit M, Ramot Y, Koffler M, Fishel B. Fibromyalgia in diabetes mellitus. Rheumatol Int. 2003; 23: 171-173.

7. Elsinger J, Plantamura A, Marie PA, Ayavou T. Selenium and magnesium status in fibromyalgia. Magnes Res. 1994 Dec;7(3-4):285-8.

8. Badyal A, Sodhi KS, Pandey R, Singh J. Serum Magnesium Levels: A Key Issue For Diabetes Mellitus. JK Science 2011; 13(3): 132-134.

9. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990 Feb;33(2):160–72.

10. Standards of Medical Care in Diabetes—2013. Diabetes Care. 2013 Jan 1;36(Supplement 1):S11.

11. Agus ZS. Hypomagnesemia. J Am Soc Nephrol. 1999 Jul 1;10(7):1616.

12. Félix FHC, Fontenele JB. Is fibromyalgia a cardiovascular disease? A comment on Martinez-Lavin’s review ‘Stress, the stress response system, and fibromyalgia’. Arthritis Res Ther. 2007; 9(5): 404.

13. Martinez-Lavin M. Biology and therapy of fibromyalgia: Stress, the stress response system, and fibromyalgia. Arthritis Res Ther. 2007;9:216.

14. Bansal V, Kalita J, Misra UK. Diabetic Neuropathy. Postgrad Med J. 2006 February; 82(964): 95–100.

15. Bansal V, Kalita J, Misra UK. Diabetic Neuropathy. Postgrad Med J. 2006 February; 82(964): 95–100.

16. Doulompakas I, Pyrpasopoulou A, Triantafyllou A, Sampanis Ch, Aslanidis S. Prevalence of musculoskeletal disorders in patients with type 2 diabetes mellitus: a pilot study. Hippokratia. 2007 Oct-Dec; 11(4): 216–218.

17. Silva MBG, Skare TL. Musculoskeletal disorders in diabetes mellitus. Rev Bras Reumatol 2012;52(4):594-609.

18. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004 May;27(5):1047-53.


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19. Mohan V, Sandeep S, Deepa R, Shah B, Varghese C. Epidemiology of type 2 diabetes: Indian scenario. Indian J Med Res 2007; 125: 217-230.

20. Vincent A, Lahr BD, Wolfe F, Clauw DJ, Whipple MO, Oh TH, et al. Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project. Arthritis Care Res (Hoboken). 2013;65: 786–92.

21. Marques AP, Santo A de S do E, Berssaneti AA, Matsutani LA, Yuan SLK. Prevalence of fibromyalgia: literature review update. Revista Brasileira de Reumatologia (English Edition). 2017 Jul 1;57(4):356–63.

22. Dhir V, Lawrence A, Aggarwal A, Misra R. Fibromyalgia Is Common and Adversely Affects Pain and Fatigue Perception in North Indian Patients with Rheumatoid Arthritis. J. Rheumatol. 2009; 36(11): 2443-2448.

23. Loevinger BL, Muller D, Alonso C, Coe CL. Metabolic syndrome in women with chronic pain. Metabolism. 2007 Jan;56(1):87-93.

24. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765.

25. Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD009318.

26. Bilbey DL, Prabhakaran VM. Muscle cramps and magnesium deficiency: case reports. Canadian family physician Medecin de famille canadien. 1996 Jul;42:1348–51.

27. Abraham GE. et al. Management of fibromyalgia: rationale for the use of magnesium and malic acid. J Nutr Med. 1992; 3:49-59.

28. Sendur OF et al. The relationship between serum trace element levels and clinical parameters in patients with fibromyalgia. Rheumatol Int. 2008; 28(11):1117-1121.

29. Wolfe F, Clauw DJ, Fitzcharles M-A,, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity. Arthritis Care & Research 2010; 62(5): 600-610.

30. Moyano S, Kilstein J, Miguel C. New diagnostic criteria for fibromyalgia: here to stay. Reumatol Clin. 2015;11:210–4

31. Heymann RE, Paiva ES, Martinez JE, Helfenstein M, Rezende MC, Provenza JR, et al. New guidelines for the diagnosis of fibromyalgia. Revista Brasileira de Reumatologia (English Edition). 2017 Jan 1;57:467–76.


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AbstractBackground & objective: Smokeless tobacco products (STP) are used without combustion. Short term effects of smokeless tobacco on blood pressure and heart rate have been observed in several studies, but there is uncertainly regarding the long term use of smokeless tobacco as a risk factor for development of hypertension.

Methods: A total of 180 adult patients of essential hypertension according to inclusion and exclusion criteria were taken. Hypertensive patients and non-hypertensive controls were assessed regarding type, quantity, route and duration of use of smokeless tobacco by asking questions.

Results: In this study, 58.33% hypertensive patients were males and 41.67% were females. The mean age in hypertensive patients was 53.74±13.02 years and in control 53.81±13.09 years. Male and female ration in hypertensive group was 1.41:1. We found that only diastolic pressure (90.178±14.205 mmHg) was marginally higher in STP users as compared to non STP users (88.258±11.301 mmHg) but was not significant statistically. In this study HDL cholesterol value was lower (p=0.0001), while total cholesterol level was higher (p=0.0001). Hypertensive patients who used STP for 1.10, 11-20, and >20 years, had OR of 0.456 (P+0.005), 1.231 (p=0.602) and 2.014 (p+0.270) respectively. However, there was a strong dose response relationship between STP and essential hypertension (chi square = 9.18, p=0.01)

Conclusion: In conclusion no significant association was seen between use of STP and essential hypertension. There was no positive association between different STP and hypertension except for red tooth powder. Different subsets of quantity and duration of STP did not have significant association with essential hypertension. However, a significant increase in the risk for hypertension was seen with increasing duration and quantity of STP (chi square, 12.06, p=0.002).

Evaluation of Smokeless Tobacco as a Risk Factor for Essential Hypertension

Original Article

annually occur due to tobacco consumption, which is expected to reach 10 million by 2025(3). In India tobacco consumption is mainly in two forms: smoked tobacco products and smokeless tobacco. Smokeless tobacco products (STP) are used without combustion and this eliminates the danger of direct exposure of toxic combustion and this eliminates the danger of direct exposure of toxic combustion compounds to the lung and other tissues of the user and of the people around. But the use of STP may result in other health hazards, local or systemic according to the way of nitrosamines (4).

In India there are several types of chewing habits featuring use of betel quid (fresh betel leaf fresh areca nut, slaked lime, catechu and tobacco), pan masala (areca nut, slaked lime, catechu and condiments), mainpuri (tobacco

Smriti Singh1

IntroductionHypertension is a very common, asymptomatic, and readily detectable and easily treatable health problem of the community, which often leads to fatal complication when left untreated (1). Of these 90-95% cases, cause is unknown or elusive, hence known as idiopathic or primary or essential hypertension and rest 5% as secondary hypertension in which cause is known (2).

Tobacco consumption is a major source of mortality & morbidity in India. Approximately 5 million deaths

1. Assistant Professor- Deptt. of Internal Medicine MLN Medical Collage E-mail: [email protected]


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and slaked lime, areca nut, camphor and claves), mawa (areca nut, tobacco and slaked lime), khaini (tobacco and slaked lime), gutka (pan masala with tobacco) and other smokeless tobaccos (mishri, gudhaku , bajjar etc)(5).

Smokeless tobacco, a leaf tobacco product provides nicotine to users through absorption across the membranes of mouth or nose. Blood pressure levels are affected by high sodium content of smokeless tobacco, as well as by 2 of its pharmacologically active ingredients: Nicotine and Licorice. The sodium content differs among brands and an increase in 24-hour urine excretion by as much as 26 to 46 mEq/L has been demonstrated after the ingestion of several different types of smokeless tobacco. Licorice inhibits the metabolism of mineralocorticoids and indirectly causes sodium retention, thereby increasing blood pressure levels (6).

Short term effects of smokeless tobacco on blood pressure and heart rate have been observed in several studies. The use of single dose of snuff or chewing tobacco increases heart rate and blood pressure to a degree similar to that observed after the smoking of a cigarette with the first few cigarette of the day and then remains elevated throughout the day and overnight, with an average of 7 beats/min above that observed in a non-smoking condition (7). However, there is uncertainty regarding the long term use of smokeless tobacco as a risk factor for development of hypertension. Various have looked at this but the results have been contradictory (8-10).

Material & MethodsIn this case control study, all patients of essential hypertension above >18 years were included. Patients of secondary hypertension, taking smokeless tobacco products and smoke producing tobacco in any form concomitantly and who had developed hypertension before habitation to smokeless tobacco products were excluded. An equal number of age and sex-matched persons without essential hypertension were selected randomly as controls

A detailed history was taken and a thorough clinical examination was done. Following investigations were carried out for hypertension, CBC, Urine R/M examination ,FBS, KFT, Fasting lipid profile, X-Ray chest PA View, ECG, 2D echolcardiography, Fundus examination and other special investigations for secondary hypertension wherever required.

STP was assessed by asking type, route and duration of use of smokeless tobacco. A former smokeless taken

smokeless tobacco products regularly but had now stopped. Non-smokeless tobacco user was defined as a person who did not take smokeless tobacco products regularly or reported occasional use of smokeless tobacco (less than one daily).

Statistical analysis: The z test was used calculated the significant of proportion while the chi square test was employed for comparison of categorical variables. Trends were calculated by chi-square for trend or by ANOVA for linearity, as applicable. Risk factors for hypertension were separately tested in a univariate logistic regression analysis. A two- tailed P value <0.05 was considered significant. Statistical analyses were performed using SPSS 17 conversion Statistical analysis.

Results430 patients of essential hypertension were screened but only 180 patients were enrolled as per inclusion criteria. An equal number of age sex matched persons without essential hypertension were selected randomly as control. In this study, 58.33% hypertensive patients were males and 41.67% were females. The mean age in hypertensive patients was 53.74±13.02 years and in control 53.81±13.09 years. Male and female ration in hypertensive group was 1.4:1. In hypertension group, there were (n=33) new hypertensive cases and (n=147) old hypertensive cases. Among hypertensive cases (n=56; 31.11%) were STP users. Baseline characteristic is shown in Table 1. We found that only diastolic pressure (90.178±14.205 mmHg) was marginally higher in STP users as compared to non STP users (88.258±11.301 mmHg) but was not significant statistically. In our study HDL cholesterol value was lower (p=0.0001), while total cholesterol level was higher (p=0.0001) in patients who used STP than those of non STP users. Different type of STP used in hypertensive and control group shown in Table 2.

DiscussionIt has been demonstrated that HDL cholesterol value was lower (p=0.00001), while total cholesterol level was higher (p=0.00001) in patients who used smokeless tobacco products than those of non STP users, which is similar to khurana et al (11-13). One third of patients in hypertensive group were STP users and OR {0.72; P=0.183} was seen for association between STP use and hypertension. Hypertensive patients who used STP for 1-10, 11-20 and >20 years, had OR 0.456(p=0.005), 1.231(p=0.602) and 2.014(p=0.270). There was no


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significant association between different subsets of duration of use of STP and hypertension.

However, red tooth powder commonly known as’ Lal Dantmanjan’ was the only STP showing significant association with hypertension. Though red tooth powder is claimed to be not containing tobacco, a laboratory test of five samples of red tooth powder that did not declare tobacco as an ingredient, found a tobacco content of 9.3-24.8 mg/gm of tooth powder. Most common red tooth powder used in our study was ‘Dabur’ lal dantmanjan, and this has been classified as STP by WHO as well (9, 18).

In this study we did not measure the amount of nicotine but measured only the total amount of STP chewed per day. It was found that OR for 0-10gm of total amount of STP chewed/day, 10.1-20 gm chewed/day were 0.641 (p=1.024), 1.193(p=0.820) and infinity (p=1) respectively i.e. no significant association was seen between different subject of quantity of STP and hypertension (chi square=9.18, p=0.01)

A significant risk for hypertension was seen with increasing duration of STP (chi square=12.06), p=0.0002).

There was some limitation to this study. In contrast to cigarettes, the nicotine obtained from a unit (quid, dip, chew or pinch) of STP is primarily determined by the product itself and size of the portion. There was difficulty in quantifying smokeless tobacco regarding nicotine content as different brands contained different quantities of STP and the exact quantity of tobacco was not mentioned on the pouch. Most of the patients were hesitant or lied about the extent and frequency of consumption. This probably because in spite of STP consumption being an acceptable vice in society, people are still hesitant to fully reveal the frequency if their consumption.

ConclusionIn conclusion no significant association was seen between use of STP and essential hypertension. There was no positive association between different STP and hypertension except for red tooth powder. Different subsets of quantity and duration of STP did not have significant association with essential hypertension. However, a significant increase in the risk for hypertension was seen with increasing duration and quantity of STP.

STP users Non STP users

Sex (male) (Female)

39 66

17 58

TG (> 150mg/dl) 211.85±36.30 109.01±22.62

LDL (<40mg/dl) 142±27.50 178.26±20.23

Hb(gm/dl) 35.05±8.89 47.83±11.54

S.creatinine (mg/dl) 12.04±1.28 1.39±1.41

FBS (mg/dl) 95±27.50 96±18.22

Table 1. Baseline characteristics of the patients demographie

Type of STP Pan masala + tobacco

Gutkha Betel quid + tobacco

Zarda Red tooth powder

Khaini Total

Hypertensive group (no. of cases)

29 (51.78%) 6 (10.71%) 3 (5.36%) 2 (3.57%) 14 (25%) 2 (3.57%) 56

Control group (no. of cases)

48 (69.56% 9 (13.04%) 1 (1.45%) 1 (1.45%) 4 (5.75%) 1 (1.45%) 69

Table 2. Type of STP used in hypertensive and control group


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Refrence:1. Henry R, George L, William J. Hypertension.

In: Hurst. 10th ed. The McGraw Hills Company, Medical Publishing Division; 2001:p. 1100-5.

2. Aubery RM. Hypertension. In: The Washington Manual of MedicalTherapeutics. 30th ed. St. Louis: Lippincott Williams and Wilkin; 2001:p. 76-95.

3. Pandey A, Patni N, Sarangi S, Singh M, Sharma K, Vellimana AK, Patra S. Association of exclusive smokeless tobacco consumption with hypertension in a adult male rural population of India: Tobacco Induced Diseases;2009:5:15.

4. Thomsen M, Ahlbom A, Bridges J, Rydzynski K. Smokeless Tobacco Products- Type, Use and Exposure. In: Health Effects of Smokeless Tobacco Products- Preliminary Report SCENIHR. 2007; 3.1:14.

5. Gandhi G, Kaur R, Sharma S. Chewing Pan Masala and/or Betel Quid –Fashionable Attributes and/or Cancer Menaces? J Hum Ecol 2005; 17(3): 161-6.

6. Benowitz NL, Porchet H, Sheiner L, Jacob P3rd. Nicotine absorption and cardiovascular effects with cigarettes and nicotine gum. Clin pharmacol Ther 198; 44: 23-8.

7. Havik RJ, Feinleib M. Hyprtension (Suppl|||): |||-1982; 121.

8. Westman E. Does smokeless tobacco cause hypertension? South Med J 1995; 88:716-20.

9. Bollinder GM, Ahlborg BO, Lindell JH. Use of smokeless tobacco: blodd pressure elevation and other health hazards found in large scale population survey. J Intern Med 1992;232:327-34..

10. Ernster VL, Grady DG, Greene JC, Walsh M, Robertson P, Daniel TE etal. Smokeless tobacco use and health effect among baseball players. JAMA 1990;264:218-24.

11. Muscat E, Harris RE, Haley N, Wynder EL. Cigarette smoking and plasma cholesterol. Am Heart J 1991; 121:141-7.

12. Gupta BK, Kaushik A, Panwar RB, Chadda VS, Nayak KC, Singh VB, Gupta R, Raja S. Cardiovascular Risk factors in tobacco chewers: A Controlled stude. J Assoc Physician India 2007;55:27-31.

13. World Health Organization, Sentinel Tobacco Use Prevalence Surveyin India, 2001, WHO SEARO, New Delhi.


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Introduction The application of nanotechnology for diagnosing and treating diseases is termed as nanomedicine. The history of nanotechnology goes back to Roman period of 4thcentury “The Lycurgus Cup”- a dichroic glass was based on colloid principle.(1) Paul Ehrlich in early20th century introduced the term “magic bullets” and the concept of targeted therapy using smaller particles. Michael Faraday in 1857 has discovered colloidal “ruby” gold, demonstrating that nanostructured gold under certain lighting conditions produces different-colored solutions. Erwin Müller in 1936 invented the field emission microscope, allowing near-atomic-resolution images of materials. In 1956, Arthur von Hippel introduced the term- “molecular engineering” as applied to dielectrics, ferroelectrics, and piezoelectrics. Professor Norio Taniguchi coined the term nanotechnology in 1974. Harold Kroto, Sean O’Brien, Robert Curl, and Richard Smalley discovered the Buckminsterfullerene (C60), more commonly known as the buckyball in 1985 which is a molecule resembling a soccer ball in shape and composed entirely of carbon, as are graphite and diamond. The team was awarded the 1996 Nobel Prize in Chemistry for their roles in this discovery and that of the fullerene class of

1. Associate Professor, Department of Medicine, University College of Medical Sciences & GTB Hospital, Delhi (Corresponding Author) E-mail: [email protected]

2. Senior consultant, Department of Medicine, Yashoda Hospital, Ghaziabad

3. Senior consultant, Department of Pediatrics, Fortis Hospital, Ghaziabad

4. Senior consultant, Department of Medicine, Saroj Super speciality Hospital, Rohini, Delhi

molecules more generally. In 1985, Bell Labs’s Louis Brus discovered colloidal semiconductor nanocrystals (quantum dots), for which he shared the 2008 Kavli Prize in Nanotechnology .In 2003 Naomi Halas, Jennifer West, Rebekah Drezek, and Renata Pasqualin at Rice University developed gold nanoshells, which when “tuned” in size to absorb near-infrared light, serve as a platform for the integrated discovery, diagnosis, and treatment of breast cancer without invasive biopsies, surgery, or systemically destructive radiation or chemotherapy. Nadrian Seeman and colleagues at New York University created several DNA-like robotic nanoscale assembly devices in 2009-2010. One is a process for creating 3D DNA structures using synthetic sequences of DNA crystals that can be programmed to self-assemble using “sticky ends” and placement in a set order and orientation. Nanoelectronics could benefit: the flexibility and density that 3D nanoscale(2)

In last 20 years or so, the advancement in this field had paved way for array of targeted drugs and imaging agents and some of which are available for clinical usage. Nanomedicine has shown promising results both in diagnostic as well as therapeutics e.g. in oncology and diseases of central nervous system.

The root of most of disease process if tracked would lead us to defect at molecular level such as defective genes or misfolded proteins or infections which will eventually lead to cellular dysfunction and manifestation of the disease. So targeting the malfunctioning molecular level by nanotechnology i.e. by particles of nano size is more specific type of treatment modality and likely to be associated with good outcome.(3) In the initial days it was thought these nanoparticles because of sheer size, nearly the size of DNA could cause targeted action at

AbstractThe application of nanotechnology for diagnosing and treating diseases is termed as nanomedicine. The purpose of the review is to know about the current applications of the nanomedicine in clinical settings, their toxicities and to explore the various evolving therapeutics and diagnostics that are still in the pipeline could be potentially used in future and also to find if this technology could ultimately replace the present.

Current Applications of Nanomedicine in Clinical Fields Review Article

Amitesh Aggarwal1, Ajay Kumar Gupta2, Vivek Goswami3, SK Mundhra4


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molecular level and avoiding unnecessary side effects. But later it was found that these nanoparticles also cause various toxicities other than the desired therapeutic effect raising the doubts of their credibility. The purpose of the review is to know about the current applications of the nanomedicine in clinical settings, their toxicities and to explore the various evolving therapeutics and diagnostics that are still in the pipeline could be potentially used in future and also to find if this technology could ultimately replace the present.

Definition There is no universally accepted definition for nanomedicine. The European Science Foundation’s (ESF) Forward Look Nanomedicine defined nanomedicine as “nano-sized tools for the diagnosis, prevention and treatment of disease and to gain increased understanding of the complex underlying pathophysiology of disease. The ultimate goal is improved quality-of-life.” (4) According to the US National Nanotech Initiative “nanotechnology is the understanding and control of matter at dimensions between approximately 1 and 100 nanometres, where unique phenomena enable novel applications. Encompassing nanoscale science, engineering, and technology, nanotechnology involves imaging, measuring, modelling, and manipulating matter at this length scale. Nanomedicine is the application of nanotechnology to medicine.” (5)

Nanotechnology is defined as “intentional design, characterisation, production and application of materials, structure devices and systems by controlling their size and shape in nanoscale range (1-100nm). Nanotechnology combined with biology becomes “nano biotechnology”(3) The field of “nanomedicine” is distinguishable as it uniquely focuses on medically related, patient-centric nanotechnologies. The broader field of “nanobiotechnology” encompasses underpinning scientific research investigating fundamental cellular mechanisms such as molecular forces, molecular motors, and cellular electrochemical phenomena, and these processes are often probed using nonhuman (plant and animal) models.(1)

Nanomaterials consists of metal atoms, nonmetal atoms or a mixtures of metal and nonmetal atoms commonly referred to as metallic, organic or semiconducting particles respectively. Their chemical properties, size, shape appear to dictate the transport of molecules to specific biological compartment and interaction between molecules.

How big can be Nanoparticle?

The particles used in nanotechnology are usually in the range of 1 to 100 nm. However there are many particles used in nanomedicines have their size greater than 100 nm and in some cases even up to 1000 nm. E.g. liposome (80 to 200nm), block copolymer micelles (50 to 200nm), nanosized drug crystals (100 to 1000nm). There is an increasing tendency to call all the nano sized medicines as “nanoparticle”. (1)

General Characteristics of NanomaterialsBecause of their size nanoparticles have a greater surface area to same volume when comparing to macromolecules. So this greater surface area allows us to attach various molecules on their surface and making them to act as carrier molecules.(6) The physical and chemical properties of individual nanoparticles are unique to make sure they perform the required specific functions. The newer generation nanoparticles act as carrying vehicle for diagnostic or therapeutic agents are designed to enter biologic barriers and mediate molecular interactions. They also have optical, electronic, magnetic and biologic properties so that it could be engineered in different combinations with different sizes, shapes and chemical structure to get a unique nanoparticle which can used in specific conditions.(7) Other characteristics required for carrier nanoparticles include biodegradability, biocompatibility, and stability inside body conditions; attain maximum concentration at pathologic site and prevention of premature degradation of drugs before reaching target site.(8)

Nanoparticles can contain metallic or organic or semi conductive particles. Examples of inorganic nanoparticles includes metals, metal oxides, metal alloy, metal phosphide, metal chalcogenide; metal oxide ceramics (e.g., zinc oxide, cadmium oxide), nonoxide ceramics (e.g., hydroxyapatite ceramics), silicates, nanowires (nanorods), semiconductor nanocrystals (QDs), nanoshells, nanorods, nanowires, inorganic fullerenes, inorganic-organic hybrid or bionanohybrid systems, and silica. They play an important role in drug discovery and delivery, discovery of biomarkers, and molecular diagnostics.(9)

Examples for organic nanoparticles are lipsomes, dendrimers, fullerenes, carbon nanotubes, etc. The porous surface of organic nanoparticles allows them function as effective carrier of drug molecules in a single carrier


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vehicle. The rate of release and specificity of the carrier molecules can be made specific by making alteration in degradation properties of polymer used and tagging with specific bio recognisable molecule respectively. There are also complex hybrid nanoparticles containing both organic and inorganic materials.

Composition and Formulation of NanoparticlesSuper-paramagnetic iron oxide crystals:

These entities are usually prepared by the alkaline co-precipitation of appropriate ratios of Fe2_ and Fe3_ salts in water in the presence of a suitable hydrophilic polymer such as dextran or poly (ethyleneglycol). This yields an iron core of 4–5 nm in diameter, which is hexagonally shaped and surrounded by dextran or poly (ethyleneglycol) molecules. These crystals possess large magnetic moments when brought into a magnetic field, thus producing a localized disturbance in magnetic field homogeneity, but the magnetic memory is lost when the field is removed. Due to such induced magnetic disturbances, there exist a large susceptibility difference between superparamagnetic iron oxide crystals and the nearby protons, causing rapid de-phasing of spins and resultant decrease in T2 relaxation times with a loss of local signal intensity. But the effects of these crystals on T1 relaxation times are relatively minor, compared with the T2 effects. These crystals are therefore “negative enhancers”.(10)

Quantum dots:

These are nano-scale crystalline structures made from a variety of different compounds, such as cadmium selenide, that can transform the colour of light, and have been around since the 1980s. Quantum dots absorb white light and then re-emit it a couple of nanoseconds later at a specific wavelength. By varying the size and composition of quantum dots, the emission wavelength can be tuned from blue to near infrared. For example, 2nm quantum dots luminesce bright green, while 5nm quantum dots luminesce red. Quantum dots have greater flexibility, when compared to other fluorescent materials, and this makes them suitable for use in building nano-scale computing applications where light is used to process information. These structures offer new capabilities for multicolour optical coding in gene expression studies, high throughput screening, and in vivo imaging.(11)

Dendrimers:

These are highly branched macromolecules with controlled near mono-disperse three-dimensional architecture emanating from a central core. Polymer growth starts from a central core molecule and growth occurs in an outward direction by a series of polymerisation reactions. Hence, precise control over size can be achieved by the extent of polymerisation, starting from a few nanometers. Cavities in the core structure and folding of the branches create cages and channels. The surface groups of dendrimers are amenable to modification and can be tailored for specific applications. Therapeutic and diagnostic agents are usually attached to surface groups on dendrimers by chemical modification.(12)

Polymeric micelles:

Micelles are formed in solution as aggregates in which the component molecules (e.g., amphiphilic AB-type or ABA-type block copolymers, where A and B are hydrophobic and hydrophilic components, respectively) are generally arranged in a spheroidal structure with hydrophobic cores shielded from the water by a mantle of hydrophilic groups. These dynamic systems, which are usually below 50 nm in diameter, are used for the systemic delivery of water-insoluble drugs. Drugs or contrast agents may be trapped physically within the hydrophobic cores or can be linked covalently to component molecules of the micelle.(13)

Liposomes:

These are closed vesicles that form on hydration of dry phospholipids above their transition temperature. Liposomes are classified into three basic types based on their size and number of bilayers. Multilamellar vesicles consist of several lipid bilayers separated from one another by aqueous spaces. These entities are heterogeneous in size, often ranging from a few hundreds to thousands of nanometers in diameter. On the other hand, both small unilamellar vesicles (SUVs) and large unilamellar vesicles (LUVs) consist of a single bilayer surrounding the entrapped aqueous space. SUVs are less than 100 nm in size whereas LUVs have diameters larger than 100 nm. Drug molecules can be either entrapped in the aqueous space or intercalated into the lipid bilayer of liposomes, depending on the physicochemical characteristics of the drug. The liposome surface is amenable to modification with targeting ligands and polymers.(14)


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Nanospheres:These are spherical objects, ranging from tens to hundreds of nanometers in size, consisting of synthetic or natural polymers (collagen, albumin). The drug of interest is dissolved, entrapped, attached or encapsulated throughout or within the polymeric matrix. Depending on the method of preparation, the release characteristic of the incorporated drug can be controlled. As with liposomes, technology also allows precision surface modification of nanospheres with polymeric and biological materials for specific applications or targeting to the desired locations in the body.(15)

Aquasomes (carbohydrate-ceramic nanoparticles):These are spherical 60–300 nm particles used for drug and antigen delivery. The particle core is composed of nanocrystalline calcium phosphate or ceramic diamond, and is covered by a polyhydroxyl oligomeric film. Drugs and antigens are then adsorbed on to the surface of these particles.(16)

Polyplexes/Lipopolyplexes:These are assemblies, which form spontaneously between nucleic acids and polycations or cationic liposomes (or polycations conjugated to targeting ligands or hydrophilic polymers), and are used in transfection protocols. The shape, size distribution, and transfection capability of these complexes depends on their composition and charge ratio of nucleic acid to that of cationic lipid/polymer. Examples of polycations that have been used in gene transfer/therapy protocols include poly-L-lysine, linear- and branched-poly (ethylenimine), poly (amidoamine), poly-amino esters, and cationic cyclodextrin.(17)

Carbon nanotubes:Carbon nanotubes belong to the family of fullerenes and consist of graphite sheets rolled up into a tubular form. These structures can be obtained either as single- (characterized by the presence of a single graphene sheet) or multi-walled (formed from several concentric graphene sheets) nanotubes. The diameter and the length of single-walled nanotubes may vary between 0.5–3.0 nm and 20–1000 nm, respectively. The corresponding dimensions for multi-walled nanotubes are 1.5–100 nm and 1–50 _m, respectively. Carbon nanotubes can be made water soluble by surface functionalization. Molecular and ionic migration through carbon naotubes can occur, thus offering opportunities for fabrication of molecular sensors and electronic nucleic acid sequencing. Carbon nanotubes

can apparently cross the cell membrane as ‘nanoneedles’ without perturbing or disrupting the membrane and localize into cytosol and mitochondria. However, the mechanisms are poorly understood.(18)

Types of applications in MedicineNanotherapeutics:Nanotherapeutics deals with therapeutic part of medicine which nanotechnology can be used as carrier molecules for delivery of drugs or themselves can be used as therapeutic agents in oncology. Therapeutic agents based on nanotechnology have advantage over the existing low molecular weight compounds with respect to following regards(19)

1. Decreased renal excretion and/or hepatic degradation, leading to prolonged circulation times.

2. Decrease the volume of distribution, leading to less accumulation healthy non-target tissues.

3. Improve the ability of drugs to accumulate at pathological sites.

4. Improve the therapeutic index of drugs, by increasing their concentration at target sites.

One particular interest is application of these agents in solid tumours. It is known that the solid tumours have leaky endothelium of 200 nm of pore size and absent lymphatics. These factors favour extravasation of nano targets specifically to solid tumour sites.(20) The same principle can also be applied in the region of inflammation where there is increased vascular permeability.

Diagnostic Nanomedicne:This area of nanomedicine is involved in the used nano modified imaging agents used in clinical diagnosis (in vivo) and also in laboratory set up where nano labelled materials improve the quality of diagnostic tests (in vitro). Clinically the application of nanoparticles in diagnosis is limited because of their stringent pharmacokinetic and elimination properties of nano sized imaging agents when administered via intra venous route.(4) Yet they give important option in the field of diagnostic oncology. In vitro application in laboratory medicine of these nanoparticles is of paramount importance. They help to simplify the readouts and improve the diagnostic threshold for the device.

Examples: detection of HCG in urinary pregnancy tests, card test for detecting malaria, HIV and cardiac


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biomarkers, Gold nanoparticles for genomic detection without PCR amplification, Screening for Single Nucleotide Polymorphism.(3)

Theranostic Nanomedicine:“Theranostic nanomedicine”, for both therapeutics and imaging, has shown to be “the right drug for the right patient at the right moment”. Here both diagnostic and therapeutic property of the nanomedicne is combined so that the carrier nano vehicle has both imaging agent and the drug.(21) The basic idea is to diagnose and treat the disease at initial stages. The diagnostic nanoparticles used most frequently in theranostics are fluorescent dyes or quantum dots, super paramagnetic iron oxides, radionuclide and heavy elements such as iodine. In the first step patients are given diagnostic nanosized radio nucleotide antibodies and look for uptake in the specific target site. Based upon uptake and likely possibility to responsiveness to therapy subset of patient selected from initial group undergo radio-immunotherapy with the same antibody coupled to a therapeutic radionuclide to set-ups in which imaging agents and chemo-therapeutic drugs are co-incorporated within a single nanomedicine formulation.(22)

It is well documented that the major cause of cancer mortality is tumor metastasis. New approaches for early stage detection of CTCs are there (circulating tumour cells) to help physicians treat patients and predict cancer progression.

By surface chemical modification, nanoparticles can be coated, functionalized, and integrated with a variety of bio conjugated moieties for selective detection and treatment.(23) Nano particles exhibit unique and versatile optical properties; there is a wide variety of contrast mechanisms for cell optical imaging. Plasmonic gold nanoparticles have been widely used as agents for detection and targeting.(24) Through the enhanced second harmonic signal by antibody conjugated gold nanoparticles, cellular imaging of single molecules has been reported. For example, iron oxide magnetic nanoparticles have been used as a contrast agent in magnetic resonance imaging and biological separation.

Selective drug delivery and encapsulation for chemotherapy:Recently, the development of functionalized uniform mesoporous silica (mSiO2) nanoparticles for drug delivery in 4T1 murine breast tumor-bearing mice has been reported.(25) Besides gold nanoparticles,

mSiO2 nanoparticle is an alternative nanoplatform for selective drug delivery. In that report, uniform mSiO2 nanoparticles were functionalized with SH-PEG, TRC105 antibody (specific to CD105/endoglin), Cu labelling and doxorubicin (DOX). After intravenous injection of functionalized mSiO2 loaded with DOX into 4T1 tumor bearing mice, an IVIS spectrum in vivo imaging system (excitation: 465 nm; emission: 580 nm) was applied to check nanoparticle distribution in the major organs. The imaging showed the feasibility to deliver a certain amount of drugs (like DOX) selectively to the tumor site in vivo through functionalized mSiO2 nanoparticles.(25)

Selective near infrared light-induced PTT (photo-thermal therapy):Gold nanoparticles absorb light and convert photon energy efficiently to heat, which makes them superior agents for PTT. Gold nanoparticle-induced PTT has been popularly reported and tested in recent years. It was first reported in 2003 for PTT of lymphocytes in vitro by gold nanoparticles with a nanosecond neodymium-doped yttrium aluminum garnet pulsed laser at 532 nm, which caused cell destruction. When irradiated with the specific laser light, functionalized gold nanomaterials will generate heat to kill cancer cells. It was found that localized temperature increased to 70-80 C throught light absorption of gold nanoparticles. Most of the cancer cells are dead after 30minutes of the nano therapy process.(26)

Selective combined therapy:Photosensitizer-conjugated nanoparticles can be coated with PEG and modified with monoclonal antibodies to selectively target the disease tissues. Through two-photon excitation of the dyes encapsulated by nanoparticles, it is possible to activate photosensitizers with low energy light that can deeply penetrate tissues. The main advantages are high drug loading ability, selective drug release, and a variety of available materials and manufacturing processes.

A gold nanorod-photosensitizer conjugate was developed for NIR photodynamic and photo-thermal combined therapy in vivo. When the gold nanorod (GNR) and the photosensitizer conjugate are targeted to the surface of the tumor tissue, the photosensitizers will be released from the GNR to tissue surface and will generate singlet oxygen. The tumor tissues can be selectively damaged by NIR laser irradiation during targeted PDT (photodynamic therapy) while minimizing phototoxic tissue destruction of surrounding healthy tissues.(27)


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Current applications in Clinical Medicine (FDA Approved)(28)

Product Company Drug Application Advantage over routine drug

Doxil Sequus pharmaceutical Doxorubicin Kaposi sarcoma in AIDS

Better tolerability

Amphocil Sequus pharmaceutical Amphotericin B Serious fungal infections

Less chance of nephrotoxicity and infusion related reactions

Ambisome Nextar pharmaceutical Amphotericin B Serious fungal infections


DaunoXome Nextar pharmaceutical Daunorubicine Kaposi sarcoma in AIDS

Longer duration of action and tumor site specificity

Abelcet The liposome company Amphotericin B Serious fungal infections


Rapamune Wyeth/Elan Sirolimus Immunosuppressant in kidney transplant

Better tolerability

Emend Merck/Elan Aprepitant Chemotherapy patient to delayed nausea and vomiting

Longer duration of action

Tricor Abbott Fenofibrate Hyper cholesterolemia, hypertriglyceridemia

Not required at the time of meal

Megace PAR pharmaceutical Megaestrol acetate Anorexia, cachexia, unexplained significant weight loss in AIDS

Longer duration of action

Abraxane American Bioscience Paclitaxel Metastatic breast cancer

Delayed cancer progression & more overall survival rate

Elastin Biosante Estradiol Mod-severe vasomotor symptomps in menopausal women

Less systemic side effects

Liposomal FormulationsLiposomes are artificial vesicles with one or more concentric layers of phospholipids and an internal aqueous core. Small unilmellar vesicles (typically 30–100 nm in diameter) are less stable than their larger counterparts (100 nm–1 μm) due to the high curvature and hence high surface tension. Liposomal formulation of amphotericin B is available for treating fungal infections thereby minimising systemic toxic effects caused by amphotericin B on other tissues. Three lipid formulations of amphotericin are approved and available for clinical use

namely Amphotec, AmBisome and Abelcet. Liposome preparation of AmB has less chance of infusion related toxicities and nephrotoxicities. Small size and negative charge on L-AmB Avoids substantial recognition and uptake by mononuclear phagocytes system therefore, less volume of distribution and clearance than AmB-lipid complex. Single dose of L-AmB results in much higher plasma level. HIV infected patients with disseminated histoplasmosis and febrile neutropenia clinical success and mortality benefit are better with L-AmB compared with conventional amphotericin B.


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The antineoplastic agents approved by FDA are Doxil, DaunoXome and Marqibo which are liposomal formulations of doxorubicin, daunrubicin and vincristine respectively. Myocet is non pegylated liposomal based formulations of doxorubicin which is marketed outside USA.

Doxil was FDA-approved for AIDS-related Kaposi’s sarcoma in 1995, for ovarian cancer in 1999, and for multiple myeloma in 2007. Major side effects are infusion related reaction, low blood counts, hand-foot syndrome and mouth sores.

DaunoXome was approved by the FDA in 1996 for treatment of Kaposi’s sarcoma. Major side effects of daunoXome are allergic reactions, pancytopenia, nausea, vomiting, discoloured urine and diarrhoea.daunoXome should not be used in patients received radiation therapy, previously received treatment with doxorubicin, doxil, daunorubicin, daunoXome or have renal, hepatic, heart diseases and poor bone marrow function. DaunoXome is pregnancy category D drug.

Marqibo was FDA-approved in 2012 for the treatment of adult patients with Philadelphia chromosome (ph) acute lymphoblastic leukemia in second or greater relapse or whose diseases has progressed following two or more anti-leukemia therapies. The most common adverse effects are infections, neuropathy, febrile neutropenia, pancytopenia.

Depocyt is liposomal formulation of cytarabine approved by FDA in the year 1999 for intra thecal or intra ventricular route for lymphomatous meningitis. Common side effects include inflammation of the sac surrounding the brain and spinal cord manifested by neck pain, neck rigidity, headache, fever, nausea, vomiting and back pain. Potential limitation of liposomal drug delivery system is drug leakage and stability in circulation.

Albumin Bound NanoparticlesAlbumin is the most abundant protein in plasma. It is a 67 kDa in weight, about 4 nm in diameter and 15 nm long, similar in size to an antibody, and has a hydrodynamic radius of about 3.5 nm. Abraxane is albumin bound paclitaxel, formed from lyophilized human serum albumin and paclitaxel. These complexes are then taken up by cells by specific receptor mediated endocytosis. Abraxane was approved by the FDA in 2005 for treatment of breast, lung, pancreatic, and small cell

lung cancers. Abraxane is given via i.v. line. Abraxane delivers high concentrations of active ingredients into cancer cells and reduces the incidence of side effects compare to original drug. Abraxane improves anticancer responses, delay cancer progression, extends overall survival more effectively, and better tolerability than taxol in advanced breast cancer. Abraxane can cause serious side effects like neutropenia (below 1500 cells/mm), neuropathy, severe infections, and hypersensitivity reactions.

MicellesApart from increasing the release time and effect, this approach may lead to increase in tolerability of drugs among drug recipients. Estrasorb™ (estradiol topical emulsion) is designed to deliver estradiol to the blood circulation following topical application of an emulsion approved by FDA in 2003.

Taxotere is docetaxel also uses micellar technology is being used as antineoplastic agent. Taxotere approved in treatment of breast cancer, non-small cell lung cancer, advanced stomach cancer, head and neck cancer and metastatic prostate cancer. Also has investigated to treat small cell cancer of lung, ovarian, bladder, pancreatic cancers, soft tissue carcinoma and melanoma. This medication is given by injection into a vein every three weeks. Anemia and leukopenia are common side effects of Taxotere.

NanotubesSomatuline depot consists of lanreotide assembled in nanotubes of 24.4 mm in diameter is indicated for the long term treatment of acromegalic patients who had an inadequate response to surgery and /or radiotherapy and for whom surgery or radiotherapy is not an option. It’s also indicated for the treatment of thyrotrophic adenomas when circulating level of thyroid stimulating hormones remains inappropriately high after surgery or radiotherapy and for the relief of the symptoms associated with neuroendocrine (particularly carcinoids) tumours. The main advantage of this formulation is when the lanreotide is delivered at elevated levels for prolonged periods it is safe and effective. Somatuline depot injection 60, 90, 120 mg is a prolonged-release formulation for deep subcutaneous injection, at 4 weeks intervals for 3 months. Common side effects are gastrointestinal discomfort, cholelithiasis and glucose intolerance.


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Nanocrystal Emend which contains aprepitant formulated as nanocrystals is approved by FDA in 2003 for treatment of chemotherapy induced nausea and vomiting. This is oral preparation and usually taken 1 hour before chemotherapy. And this medication is also used to prevent nausea and vomiting after surgery.

Tricor is nano crystallized formulation of fenofibrate is approved by FDA in 2005 for hypercholesterolemia. This new formulation is as safe and efficacious as the previous formulation. The new tablet strengths, 48 and 145 mg, replaced the 54 and 160 mg tablets. The Nanocrystal technology eliminates the requirement of this drug with a meal.

FDA has approved Megace ES which contains nanocrystallized megasterol acetate for AIDS induced anorexia. Megace is a synthetic, antineoplastic and progestational drug supplied as tablets for oral administration containing 20 and 40 mg magestrol acetate. It is also indicated for the palliative treatment of advanced carcinoma of breast or endometrium.

Rapamune containing sirolimus also uses nanocrystal technology which is approved by FDA as immunosuppressant for post renal transplant patients. The anti-proliferative effect of Rapamune has been used in conjunction with coronary stent to prevent restenosis following balloon angioplasty. Rapamune is being investigated for treatment for tuberous sclerosis, Alzheimer’s, muscular dystrophy, marijuana induced amnesia, systemic lupus erythematosus, in future may show promising results.

PolymersOncaspar is PEGlyated asaparginase is approved by FDA in july 24, 2006 for the first line treatment of acute lymphocytic leukemia as a component of a multi-agent chemotherapy regimen. The advantage of Oncaspar over L-asparginase are it can be used in patients with hypersensitivity to native forms of L-asparaginase, unique therapeutic advantages of sustained duration and prolonged effect resulting in enhanced convenience for patients.

Metallic NanometerialsTwo MRI contrast nano agents namely Feridex and Resovist had been approved by FDA for imaging of liver and spleen. Feridex is a aqueous colloid of supramagnetic iron oxide particle coated with dextran and Resovist

is iron oxide particles coated with carboxydextran for intravenous (i.v.). The amount of iron contained in a single dose is 39 mg for a 70 kg individual. Iron in Feridex and Rsovist are taken up by reticuloendothelial cells and enter the usual iron metabolism, but are not retained in lesions lacking kupffer cells. Consequently, there are significant differences in T2 relaxation between normal tissue and lesions, resulting in increased lesion conspicuity and detectability. Feridex and Rosavist also used for evaluating macrophage activities in some inflammatory lesions, but their clinical value further to be confirmed. The difference being that Resovist can be administered as a rapid bolus (and thus can be used with both dynamic and delayed imaging), whereas Faridex needs to be administered as a slow infusion and is used solely in delayed phase imaging. Back pain and vasodilatation are the adverse effects noted with Feridex.

Verigene is nanosized gold has been approved by FDA for in vitro genetic analysis. Enables high specificity for both nucleic acid and protein detection, reduce background noise, which in turn creates an enhanced assay signal. Technology of gold nanoparticle is extremely stable, a long shelf-life and are non toxic.

Arsenic trioxide is approved by the US FDA for the treatment of patients with acute promyelocytic leukemia.

Safety and Toxicity ConcernsNanotechnologies offer exciting opportunities for targeted drug delivery which is anticipated to increase the efficacy of the drug and reduce potential side-effects, through the reduction of the dose of the drug in bystander tissues and an increase of the drug at the desired target site. Nevertheless, understanding whether the nano-scale carriers themselves may exert adverse effects is of great importance. There are two sides to the coin. The small size may enable nanoparticles to negotiate various biological barriers in the body which could, in turn, give rise to unexpected toxicities. On the other hand, the potential of nanoparticles to cross barriers can also be exploited for drug delivery. Determining the fate of nanoparticles following their therapeutic or diagnostic application is critical: are nanoparticles excreted, or biodegraded, or do they accumulate, potentially leading to harmful long-term effects.

In 2006, several leading scientists proposed five grand challenges that need to be met if we are to achieve safe and sustainable development of the nanotechnologies.(29)


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The challenges: 1. To monitor nanomaterial exposure in air and water.

2. Develop and validate methods to evaluate the toxicity of nanomaterials.

3. Develop models for predicting the impact of nanomaterials on the environment and human health.

4. Develop robust systems for evaluating health and environmental impact of nanomaterials over their entire life cycle.

5. Develop strategic programs that enable relevant risk focused research,were chosen to stimulate strategic research relevant to the safety of nanotechnology.

The safety of any new drug or drug carrier always has to be carefully assessed, through preclinical and clinical trials, prior to its approval by the relevant regulatory agencies In addition, the concern over the potential toxicity of nanomaterials in medicine should be tempered

by the understanding that all drugs, if applied at the wrong dose or in a susceptible patient, may give rise to toxicity.

Many factors such as size, inherent properties, dosage and surface chemistry may affect nanoparticle toxicity

Size: A reduction in the size of nano-sized particles results in an increase in particle surface area. Therefore more chemical molecules may attach to this surface, which would enhance its reactivity and result in an increase in its toxic effects.(30)

Inherent properties and surface chemistry: Chemical components of the particle surface have important effects on nanoparticles as they can react with metals. Iron can be affected by nanoparticles, which increases the induction of ROS in the free cell system. Which give rise to inflammation, cell destruction, and genotoxicity. (31)

Dosage: Toxicity and other responses depend on the prescribed dosage and substances used. Research has shown that a high dose of nanoparticles in small or big particles could be harmful to health.(31)

Liposomes show great possibilities as drug carriers and are already used as drug delivery systems in treatment of cancer, but they are occasionally known to induce complement activation which can lead to hypersensitivity reactions.(32)

There is a potential risk when using nanomaterials, a consideration supported by findings of toxicological effects of metal oxides, carbon nanotubes or combustion particles that may promote inflammation, cytotoxicity and genotoxicity in lungs after airway exposure and to promote allergic sensitization. Arsenic used in treatment of acute promyelocytic leukemia, can cause bladder or lung carcinoma. Nanosilver crystals are used in bandages as antimicrobial agents, but the use of silver nanoparticles depends on counteracting their positive (antimicrobial effect) and negative (cellular toxicity) effects.(33)

Recent study demonstrated that aspiration of single-walled carbon nanotubes elicited an unusual inflammatory response in the lungs of exposed mice with a very early switch from the acute inflammatory phase to fibrogenic events resulting in pulmonary deposition of collagen and elastin. This was accompanied by a characteristic change in the production and release of proinflammatory to anti-inflammatory profibrogenic cytokines, decline in pulmonary function, and enhanced susceptibility to infection.(34)

Future Prospects The emergence and existence of nanotechnology is a reality now and the governments have begun to envision nanotechnology’s enormous potential. Our near-term ability to structure materials and devices at the molecular scale brings enormous immediate benefits and will revolutionize the research and practice of medicine. Early theoretical and experimental studies of the biocompatibility of nanomaterials and advanced nanodevices have begun.

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8. Gholap AD. Translational Nanomedicine: Status Assessment and Opportunities. 2012.

9. Sekhon BS, Kamboj SR. Inorganic nanomedicine--part 1. Nanomedicine : nanotechnology, biology, and medicine. 2010;6(4):516-22.

10. Kucheryavy P, He J, John VT, Maharjan P, Spinu L, Goloverda GZ, et al. Superparamagnetic iron oxide nanoparticles with variable size and an iron oxidation state as prospective imaging agents. Langmuir. 2013;29(2):710-6.

11. Ghai I, Ghai S. BIO-FUNCTIONALIZED QUANTUM DOTS EXPLORING AND EXPANSION OF NANOMEDICINE. Inventi Impact: NDDS. 2014.

12. Kannan RM, Nance E, Kannan S, Tomalia DA. Emerging concepts in dendrimer-based nanomedicine: from design principles to clinical applications. Journal of internal medicine. 2014.

13. Tong R, Tang L, Ma L, Tu C, Baumgartner R, Cheng J. Smart chemistry in polymeric nanomedicine. Chemical Society Reviews. 2014;43(20):6982-7012.

14. Al-Jamal WT, Kostarelos K. Liposomes: from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine. Accounts of chemical research. 2011;44(10):1094-104.

15. Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids and Surfaces B: Biointerfaces. 2010;75(1):1-18.

16. Sutar Y, Mokale V. Aquasomes: A Promising Nanocarrier for Hydrophobic Drug Delivery. Inventi Rapid: NDDS. 2012.

17. Tros de Ilarduya C, Sun Y, Düzgüneş N. Gene delivery by lipoplexes and polyplexes. European journal of pharmaceutical sciences. 2010;40(3):159-70.

18. De Volder MF, Tawfick SH, Baughman RH, Hart AJ. Carbon nanotubes: present and future commercial applications. Science. 2013;339(6119):535-9.

19. Rizzo LY, Theek B, Storm G, Kiessling F, Lammers T. Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications. Current opinion in biotechnology. 2013;24(6):1159-66.

20. Qian X, Ansari D, Nie S. Vivo tumor targeting and spectroscopic detection with surface-enhanced raman nanoparticle tags. Google Patents; 2012.

21. Muthu MS, Mei L, Feng S-S. Nanotheranostics: advanced nanomedicine for the integration of diagnosis and therapy. Nanomedicine: nanotechnology, biology, and medicine. 2014;9(9):1277-80.

22. Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. Journal of clinical oncology. 2011;29(17):2416-23.

23. Hyun K-A, Lee TY, Jung H-I. Negative enrichment of circulating tumor cells using a geometrically activated surface interaction chip. Analytical chemistry. 2013;85(9):4439-45.

24. Poon Z, Chen S, Engler AC, Lee Hi, Atas E, von Maltzahn G, et al. Ligand-Clustered “Patchy” Nanoparticles for Modulated Cellular Uptake and In Vivo Tumor Targeting. Angewandte Chemie International Edition. 2010;49(40):7266-70.

25. Chen F, Hong H, Zhang Y, Valdovinos HF, Shi S, Kwon GS, et al. In vivo tumor targeting and image-guided drug delivery with antibody-conjugated, radiolabeled mesoporous silica nanoparticles. ACS nano. 2013;7(10):9027-39.

26. Gollavelli G, Ling Y-C. Magnetic and fluorescent graphene for dual modal imaging and single light


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31. Zhang X-Q, Xu X, Bertrand N, Pridgen E, Swami A, Farokhzad OC. Interactions of nanomaterials and biological systems: Implications to personalized nanomedicine. Advanced drug delivery reviews. 2012;64(13):1363-84.

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induced photothermal and photodynamic therapy of cancer cells. Biomaterials. 2014;35(15):4499-507.

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IntroductionAllergic bronchopulmonary aspergillosis (ABPA) is a disorder caused by hypersensitivity to Aspergillusantigens, and is currently the best recognized manifestation of Aspergillus-associated hypersensitivity disorders. The exact prevalence of ABPA is not known but contemporary estimates suggested that ABPA complicates 1 to 11% of all chronic cases of bronchial asthma1,2. Alok Nathetal in their latest study on 350 patients found the prevalence of Aspergillus hypersensitivity and ABPA to be 35.1% and 21.7%, respectively.3

Patients with ABPA may present with recurrent asthma exacerbations, expectoration of dark brown mucus plugs, hemoptysis, or systemic symptoms such as fever, anorexia, malaise, or weight loss. Patients with ABPA present with diverse radiographic manifestations, including finger-in-glove and toothpaste opacities, air-fluid levels from dilated bronchi, and tramline shadows from edematous bronchial walls4. High resolution CT

AbstractAllergic bronchopulmonaryaspergillosis (ABPA) is a common but frequently misdiagnosed clinical condition. It is usually diagnosed in patients with a long standing history of asthma. Patients with ABPA can have variety of radiological presentations. Very rarely, lung masses have been reported. We hereby report a case of ABPA in whom a lung mass was the presenting radiological manifestation leading to consideration of lung cancer as a differential diagnosis. The establishment of ABPA as the underlying diagnosis led us to treat him with oral corticosteroids which were followed by complete resolution of the mass like opacity. The present case highlights that ABPA should be considered as a differential diagnosis whenever encountering a patient with lung mass and history of asthma with raised eosinophil counts.

Allergic Bronchopulmonary Aspergillosis Presenting as a Pulmonary Mass-A Case Report

Case Report

Rajendra Prasad1, Anamika Verma2, Saurav Pandey3, Rishabh Kackar4, Jaskirat Singh5, Nikhil Gupta6.

characteristically shows central bronchiectasis, mucus-filled bronchi (bronchoceles), consolidation, and tree-in-bud appearance of centri-lobular nodules5.Pulmonary masses in ABPA are uncommon but have been described in the literature6-8.Proximal bronchoceles may simulate hilar mass9.This case is reported because of its rare occurrence.

Case ReportA 38 year old male, known case of asthma for 15 years presented with cough with expectoration, shortness of breath, chest tightness and fever for 15 days. There was no history of haemoptysis, expectoration of brownish black mucus plugs or loss of weight or appetite. On general physical examination, the patient had respiratory rate of 24/min without any use of accessory muscles of respiration. Expiratory polyphonic rhonchi were audible over bilateral lung fields. Examination of rest of the systems was normal. The patient was prescribed antibiotics and was suspected to have pulmonary mass by outside doctors on the basis of chest radiograph for which he was referred to our center. The Chest Radiograph (figure 1) showed an irregular shaped opacity in Right Lower zone mimicking pulmonary mass. High resolution computed tomography of thorax showed Homogenous opacity in Right Lower lobe resembling pulmonary mass (figure2) andcentral bronchiectasis(figure3). Laboratory

1. Department of Pulmonary MedicineEra’s Lucknow Medical College and Hospital (Corresponding Author) E-mail: [email protected]

2-5 Department of Pulmonary MedicineEra’s Lucknow Medical College and Hospital

6. Department of General Medicine Dr Ram Manohar Lohiya Institute of Medical Sciences, Lucknow.


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investigations showed the Absolute Eosinophil count of the patient was raised(1120 cells/cumm),Total Serum IgE of the patient was elevated(6121kUA/L).Aspergillus specific IgG was elevated (156.80 U/ml) and Aspergillus specific IgE was elevated(37.30 kUA/L) and Immediate Aspergillusfumigatus skin prick test

Figure1. Posteroanterior chest radiograph demonstrating mass like rounded opacity in the right lower zone.

Figure 2. Contrast enhanced CT scan of the thorax showing irregular mass like opacity in right lower lobe with satellite lesions with central bronchiectasis.

was positive(Type I).Patient was diagnosed as allergic bronchopulmonaryaspergillosis. Patient was treated with oral corticosteroids with a dose of 0.5mg/kg body weight for 2 weeks and 0.5mg/kg body weight alternate day for 3 months and showed marked improvement in clinical, laboratory and radiographic findings (figure 4)


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Figure 3. Contrast enhanced CT scan of the thorax ( lung window ) showing central bronchiectasis.

Figure 4. Posteroanterior chest radiograph demonstrating clearing of the rounded opacity after taking oral corticosteroids for 3 weeks.


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DiscussionABPA is a complex immune hypersensitivity reaction that manifests when the bronchi become colonized by Aspergillus, which causes chronic inflammation, then bronchiectasis, fibrosis, and, ultimately, respiratory failure. Although there are 200 species of Aspergillus, only few like A. fumigatus, A. flavus,andA. niger have been reported to cause ABPA. The Rosenberg criteria10are most widely used for diagnosis and include 8 major and 3 minor criteria. The major criteria include asthma, roentgenographic evidence of pulmonary opacities, skin test positive for aspergillus (Type 1 reaction), eosinophilia, precipitating antibodies (IgG) against aspergillus in the serum, elevated serum IgE levels (>1,000 IU/mL), central bronchiectasis and elevated serum Aspergillusfumigatus- specific IgG and IgE. The minor criteria include presence of Aspergillus in sputum, expectoration of brownish black mucus plugs and delayed skin reaction to Aspergillus antigen (type III reaction).If 6 of the 8 major primary criteria are met, the diagnosis is certain.

Greenberger 199711 criteria do not differentiate into major and minor diagnostic criteria. Eight diagnostic criteria are laid down to detect ABPA .These criteria are Asthma (mild or severe) or cystic fibrosis, Immediate cutaneous reactivity to aspergillus antigen, Current or previous pulmonary infiltrates, Elevated total IgE concentration (>l mg/L), Precipitin antibodies to A. fumigatus, Peripheral blood eosinophilia, Elevated serum IgE and / or IgG-against A. fumigatus and Proximal bronchiectasis.

Recently proposed diagnostic criteria for allergic bronchopulmonary aspergillosis by International Society for Human and Animal Mycology (ISHAM)12includes;

Predisposing conditions: Bronchial asthma, cystic fibrosis.

Obligatory criteria (both should be present):

1. Type I Aspergillus skin test positive or elevated IgE levels against Aspergillusfumigatus.

2. Elevated total IgE levels (> 1000 IU/mL), If the patient meets all other criteria, an IgE value < 1000 IU/mL may be acceptable.

Other criteria (at least two of three should be present):

1. Presence of precipitating or IgG antibodies against A. fumigatus in serum.

2. Radiographic pulmonary opacities consistent with ABPA

3. Total eosinophil counts> 500 cells/µL in steroid naıve patients (may be historical)

A wide spectrum of radiographic changes can be seen in patients with ABPA 5, including transient migratory radiographic opacities secondary to eosinophilic pneumonia4. High-resolution CT characteristically shows central bronchiectasis, mucus-filled bronchi, consolidation, and centri-lobular nodules5. Other manifestations include segmental or lobar collapse, pleural effusion, and spontaneous pneumothorax5.A characteristic radiographic finding in ABPA is high-attenuation mucus.

The presentation of ABPA as pulmonary masses (as seen in our patients) is distinctly uncommon6-8. These masses are usually attributed to mucus plugging of bronchi and distal accumulation of secretions6-7,as seen in our patient, or large bronchoceles (mucus-filled dilated bronchi), which appear as masses but with no proximal obstruction 8.Another mechanism, is probably inflammatory eosinophilic parenchymal consolidation, without endobronchial involvement, appearing as pseudotumor. Eosinophilic organizing pneumonia due to adjoining intense bronchial inflammation led to pseudotumor formation. Though bronchoceles are classically seen in ABPA, reversible bronchoceles are almost pathognomonic of ABPA13. The presence of hyperdense mucus is the most characteristic (if not pathognomonic) finding of ABPA, and occurs in almost 19% of these patients. The high-attenuation calcium salts generally indicate chronicity and negate an acute event. In our patient, the quick disappearance of the mass after initiation of treatment indicates an acute event which dramatically responded to treatment.

It is important to note that ABPA can be diagnosed in patients without history of asthma unlike our case. This is particularly important because in these patients, presence of a lung mass can lead to strong consideration of lung cancer as a diagnostic possibility and lead to invasive diagnostic procedures to establish an accurate diagnosis. Sanchez-Alarcoset al7 reported a 65 year old male smoker patient without any history of asthma, who underwent right upper lobectomy due to the presence of radiological appearance of a lung mass. The diagnosis of ABPA was delayed for one year following surgery.


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ABPA can present as pulmonary mass lesion and must be considered in the differential diagnosis in patients presenting with history of asthma. High-attenuation density within these masses can help narrow the differential diagnosis. It is important to consider ABPA in the diagnostic algorithm of pulmonary masses, because treatment with glucocorticoids is associated with excellent outcomes, as seen in our patient.

Refferences:1. Maurya V, Gugani HC, Sarma PU, Madan T, Shah A.

Sensitization to aspergillus antigens and occurrence of allergic bronchopulmonary aspergillosis in patients with asthma. Chest 2005; 127: 1252-9.

2. R. Prasad, R. Garg, Sanjay & R. Dixit : A Study on Prevalence of Allergic Bronchopulmonary Aspergillosis in Patients of Bronchial Asthma . The Internet Journal of Pulmonary Medicine. 2008 Volume 9 Number 2

3. Nath A, Khan A, Hashim Z, Patra JK. Prevalence of Aspergillus hypersensitivity and allergic bronchopulmonary aspergillosis in patients with bronchial asthma at a tertiary care center in North India. Lung India 2017,34:150-4

4. Thompson BH, Stanford W, Galvin JR, Kurihara Y. Varied radiologic appearances of pulmonary aspergillosis. Radiographics 1995;15(6):1273-84.

5. Shah A. Allergic bronchopulmonary and sinus aspergillosis: the roentgenologicspectrum. Front Biosci 2003;8:e138-e146.

6. Cote CG, Cicchelli R, Hassoun PM. Hemoptysis and a lung mass in a 51-year-old patient with asthma. Chest 1998;114:146-8.

7. Sanchez-Alarcos JM, Martinez-Cruz R, Ortega L, Calle M, Rodriguez-Hermosa JL, Alvarez-Sala JL. ABPA mimicking bronchogenic cancer. Allergy 2001;56:80-1.

8. Coop C, England RW, Quinn JM. Allergic bronchopulmonaryaspergillosis masquerading as invasive pulmonary aspergillosis. Allergy Asthma Proc 2004;25(4):263-6.

9. Agarwal R, Reddy C, Gupta D. An unusual cause of hilarlymphadenopathy.Lung India 2006;23(2):90-2.

10. Rosenberg M, Patterson R, Mintzer R, Cooper BJ, Roberts M, Harris KE. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonaryaspergillosis. Ann Intern Med 1977;86:405-414.

11. Patterson R, Greenberger PA, Radin RC et al. Allergic bronchopulmonary aspergillosis-staging as an aid to management. Ann Intern Mad 1982; 96:286-91.

12. R. Agarwal , A. Chakrabarti , A. Shah.Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy.2013,850–73.

13. Lemire P, Trepanier A, Hebert G. Bronchocele and blocked bronchiectasis. Am J Roentgenol 1970;110:687-93.


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Hemorrhagic infarct- A Rare Neurological Outcome of Plasmodium Vivax Cerebral Malaria: a Case Report

Case Report

A. Pandey 1, P.K. Maheshwari2, M.Chaturvedi3

1. Associate Professor, P.G. Dept. of Medicine, S.N. Medical College, Agra (INDIA) (Corresponding Author) E-mail: [email protected]

2. Associate Professor, P.G. Dept. of Medicine, S.N. Medical College, Agra (INDIA). (Co-Author)

3. Associate Professor, P.G. Dept. of Medicine, S.N. Medical College, Agra (INDIA).

AbstractMalaria is an important tropical disease. Cerebral involvement is the most important complication in Plasmodium falciparum & rarely in Plasmodium Vivax infection, with a mortality rate of up to 50% [15].

Plasmodium Vivax cerebral malaria presenting as hemorrhagic infarct is uncommon presentation, here we are reporting one such case in a young female patient from malaria endemic zone (Agra).

As far as to our knowledge, this is the first case report of this neurological sequel (hemorrhagic infarct) from India & probably this is the only case report where causative agent is Plasmodium Vivax previous case report has shown association with P. Falciparum.

Keywords - Cerebral malaria, Endemic, Plasmodium Vivax, Hemorrhagic Infarct.

IntroductionMalaria is a mosquito borne infectious disease of humans & other animals caused by parasitic protozoans of genus plasmodium of five species. Commonly this disease is transmitted via bite of infected female anopheles mosquito.

Cerebral malaria is defined as severe P. falciparum malaria presenting with neurological symptoms including coma. It manifests as diffuse symmetrical encephalopathy & is associated with retinal hemorrhage with pupillary dilation, hepatosplenomeagly, anemia, hypoglycemia, convulsions, hemoglobinuria with renal failure may occur. Approx. 10% of children surviving cerebral malaria have a persistent language deficit.

It is a life threatening complication seen in 2% of malarial cases particularly in P. falciparum infection [1]. There is an estimated mortality rate of between 15% to 25% even with appropriate treatment & intensive care & mortality may reach 50% if more than 10% RBCs are parasitized[13].

Only 45 cases of CNS P. Vivax Malaria are reported in scientific literature since 1920, about half of these cases have occurred in children [2,3]. Any patient infected with P. vivax who exhibits severe malaria is presumed to be suffering multiple infection. In patient with cerebral malaria, loss of unconsciousness can develop very rapidly, most patient are already in deep coma by the time they reach to the hospital[4].

Case historyA 16 yr old female was admitted with complaint of fever moderate to high grade, on & off from 8 days associated with chills and rigors which relieved on medications but not associated with headache, vomiting, rashes. History of altered sensorium was present from 5 days. There was no history of seizures, trauma, bleeding manifestation, cough with expectoration, decreased urine output, burning micturition. There was no history suggestive of DM/HTN/ATT intake.

On examination, her GC was low, vitals were within normal limit. Pallor, icterus, cyanosis, clubbing, edema, LNP were absent. On systemic examination, Respiratory system, CVS, P/A were within normal limit.

CNS examination, patient was not oriented to T/P/P, Pupils had normal size normal reaction, NR/KS was absent, Planters were B/L extensor, Deep tendon reflexes were decreased B/L and her GCS= E4V1M1=6.

At the time of admission, her laboratory parameters were as follows-


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Hb=10gm, TLC = 9800mm3, N89L10E1,

P/C=2,70,000mm3, S.Bill(T)=1.1,

B.Urea=24mg%, S.Creat=0.8mg%.

Her RBS was 74, after giving D25% 100cc iv stat it became 134.

S.Na+/K+ was normal but ionic calcium was 0.84, after calcium supplementation it became 1.12.

At the time of discharge her laboratory parameters were as follows-

Hb=10.2gm, TLC=8200mm3,

N84L14E2, P/C=1,90,000mm3,

B.Sugar/B.Urea=110/40

S.Na+/K+/i.Ca+2=141.5/3.68/1.22. Her coagulation profile, renal function test, liver function test, urinalysis was within normal limit.

CSF examination was performed twice, earlier one showed the picture of TLC=110cells/mm3, DLC=N80L20, Protein=130mg/dl, Glucose=60mg/dl and repeated CSF examination was done after 13 days which was normal.

Rapid card test for malarial antibody was reactive for P.vivax.

Plain & contrast CT head- Diffuse hypodensity and edema is seen involving B/L thalami, mid-brain, and pons with significant post contrast enhancement. Mild compression of 3rd ventricle is seen. Effacement of the perimesencephelic cisterns is seen. Subtle effacement of B/L cerebral sulci noted within mild leptomeningeal enhancement. (Fig 1)

B/L symmetrical infarction of the thalami has been seen in internal cerebral vein thrombosis, Japanese Encephelitis

and occlusion both paramedian thalamic & mesencephelic arteritis caused by atherosclerosis or TBM [5,14].

MRI Brain- Multiple, multifocal hyperintense at B/L thalami, Pons, mid-brain, post limb of B/L internal capsule causing diffuse swelling .This show diffuse restriction on DW images.Focal ill-defined areas is noted at the centre of these hyperintensities which appear hyperintense on T1W & hypointense on T2 & bloom on GRE images suggestive Hemorrhagic infarct. (Fig 2)

Fig 1: CT Head showing Diffuse hypodensity and edema in B/L Thalami, Midbrain, Pons (white arrow) with mild leptomeningeal enhancement (red arrow).

Fig 2: MRI ( Brain) Multiple, multifocal hyperintense at B/L thalami, pons, midbrain, posterior limb of B/L internal capsule causing diffuse swelling with focal hypointense area on T2W images suggestive of hemorrhagic infarct.

A case report by millan[6] et al & a case series by cordoliani[1] et al both demonstrate hemorrhages & infarction in single cases. The interpretation was based on T1 & T2 weighted & FLAIR images.

Hemorrhagic or bland infarcts in the basal ganglia, thalamus, cerebellum are known to occur. An isolated Pontine infarct[15] & a hemorrhagic infarct in parietoccipital lobe have been reported as well[6].

Hemorrhagic infarct as seen in this case has been reported very rare before in P.falciparum cerebral malaria [6].

TreatmentBefore reaching to hospital, this pt. had already been treated with quinine hydrochloride injections in private hospital. Here we started the treatment with 7 day coarse of Injection Artesunate 60mg 2vial iv at 0, 12, 24 then OD along with clindamycin 600mg iv 12 hourly according to WHO guideline[12], iv paracetamol etc. Patient responded well with this treatment. Her GCS become 14 from 6 & discharged satisfactorily from the hospital.

DiscussionCerebral damage in malaria is due to vascular sequestration of parasitized erythrocytes & potential cerebral toxicity by cytokines [7,10]. RBCs parasitized by P.falciparum


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adhere to capillary endothelium at intraerythrocytic phase of life cycle of parasite. This phenomenon occurs mostly in brain vessels particular in cortical & perforating arteries resulting in perivascular ring like hemorrhages so called Durk’s Granulomas & white matter necrosis[8,9]. Released cytokines could lead to vascular engorgement & vasodilation leading to cerebral edema & ischemia[16]. If effective treatment for cerebral malaria is not introduced, these changes may become severe enough to lead to irreversible necrotic & hemorrhagic lesions of perivascular myelin similar to lesion caused by fat emboli[16,17]. Patient become drowsy and disoriented; hallucinations are common. As the disease process advances, level of consciousness deteriorates and patient becomes comatose [11]. These infarcts have resulted in residual neurological deficits such as hemiparesis, quadriparesis, blindness, epilepsy & aphasia.

Conclusionn addition to diffuse brain swelling,hemorrhagic infarcts can be seen on MR examinations obtained during the course of Plasmodium Vivax cerebral malaria. The diagnosis of cerebral malaria should be strongly considered when acute hemorrhagic infarctions, particularly in the thalami, are encountered in patients with constitutional symptoms with or without history of travel to an endemic area.

References:1) Cordoliani YS, Surrazin JL, Felten D, Caumes E,

Leveque C, Fisch A. MR of cerebral malaria. AJNR Am J neuroradiol 1998;19:871-4.

2) Ozen M, Gungor M, Atambay M, Daldal N. Cerebral malaria owing to P.vivax 2006;26:141-4.

3) White NJ. Malaria In, Cook GC, Zumla AI editors.

4) Garg RK. Cerebral Malaria. JAPI 2000;48:1004-13.

5) Kumar S, Mishra UK, Kalitha J, Salwani V, Gupta RK, Gujral R. MRI in Japanese encephalitis neuroradiology 1997;39:180-184.

6) Millan JM, Sen Millan JM, Munoz M, Navas E, Lopez-Velez R, CNS complication in acute malaria. MR findings AJNR Am J neuroradiol 1993;14:493-4.

7) Turner GD, Morrison H, Jones M, Davis TM, Looareesuwan S, Buley ID et al. An Immunohistochemical study of the pathology of fatal malaria. Evidence of widespread endothelial activation & potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am J Pathol 1994;145:1057-69.

8) Toro G, Roman G, Cerebral Malaria. A disseminated vasculomyelinopathy. Arch Neuro 1978;35:271-5.

9) Janota I, Doshi B. Cerebral Malaria. 1979;32: 769-72.

10) Turner G. Cerebral Malaria. Brain Pathol 1997;7:569-582.

11) Khadilkar SV, Sorabjee JS. Cerebral Malaria. Bombay Hosp Jr 1996;38:23-25.

12) World Health Organization: guidelines for the treatment of malaria, 2nd edition Geneva, WHO 2010. (who.int/malaria/publications/atoz/9789241547925/en/)

13) Hoffman SL, Rustama D, Punjabi NH, et al. High dose Dexamethasone in quinine treated patients with Cerebral malaria: a double blind, placebo control trial. J Infect Dis. 1988;158:325-331.

14) Jourdan C, Terrier A, Altra F. Sickle cell anemia & Internal cerebral vein thrombosis. Ann Fr Anesth Reanim 1997;16:967-969

15) Kampfl AW, Birbaner GG, Pfausler BE, Haring HP, Schmutzhard E. Isolated pontine lesion in algid cerebral malaria: Clinical features, management & magnetic resonance imaging findings. Am J Trop Med Hyg 1993;48:818-22.

16) Patankar TF, Karnad DR, Shetty PG, Dessai AP. Adult Cerebral malaria: prognostic importance of imaging findings & correlation with postmortem findings. Radiology 2002;224:811-16.

17) Janota I, Doshi B. Cerebral Malaria in United Kingdom. J Clin Pathol 1979;32:769-72.


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Cervical Spondylosis with Reversal of Lordosis – A Pictorial CMEPictorial CME

A. Pandey1, M.Chaturvedi2, P.K. Maheshwari3

1. Associate Professor, P.G. Dept. of Medicine, S.N. Medical College, Agra (INDIA).

2. Professor, P.G. Dept. of Medicine, S.N. Medical College, Agra INDIA). (Corresponding Author) E-mail: [email protected]

3. Professor, P.G. Dept. of Medicine, S.N. Medical College, Agra INDIA).

Introduction38 years old female came with complaints of severe pain in the neck, severe restriction of neck movement, loss of sleep because of same from 8 days, patient had mild pain during neck movement from last 3 months, for which she went to some chiropractitioner, he did some joint adjustment and manipulation, thereafter the pain and stiffness in the neck increased. No past history of injury, or surgery of neck, no radiation to of pain or numbness to other parts of your body, no history of bowels or bladder involvement. On examination cervical kyphosis present as examined clinically by C- shaped curve over neck, range of movement of cervical spine painful and markedly reduced in all planes. Rest loco motor system, CNS, CVS, Respiratory system examinations were within normal limits. X-Ray cervical spine revealed cervical spondylitis with reversal of lordosis (cervical kyphosis)When viewed from the side, the normal cervical spine has lordosis. Kyphosis is a term used to describe a type of abnormal curve in the cervical spine. A kyphotic curve looks like the letter “C” with the opening of the C pointing towards the front. This type of curve is the opposite of a normal lordotic curve, which has the opening facing towards the back. The larger the abnormal curve, the more serious the problem. Several different conditions namely spinal surgery like laminectomy, degenerative changes,

Figure: X-R ay cervical spine (lateral view) showing reversal of lordosis.

congenital defects, trauma, tumors, infections, ankylosing spondylitis and radiation therapy at early stages of life can lead to this problem. The symptoms and severity of kyphosis vary. Symptoms range from minor changes in the shape of spine, to severe deformity, neurologic deficits, and chronic pain. If the kyphosis is severe, pressure can occur on the spinal nerve roots or spinal cord. This can cause weakness in the arms or legs, loss of grip strength, difficulty walking due to spasticity in the legs or quadriplegia. Bowel or bladder control may be lost. The most common tests used to diagnose cervical kyphosis are X-ray and MRI. Treatment of this deformity depends largely on whether there

is pressure on the spinal cord. Surgery in form of spinal fusion combined with segmental instrumentation is advisable if there is spinal compression. If the cervical kyphosis is primarily causing pain and no neurological complaints, pain relievers and neck brace can be tried for a short period of time along with graded physical therapy program.

References: 1) Harrison DD, Janik TJ, Troyanovich SJ, et al: Com-

parisons of lordotic cervical spine curvatures to a theoretical ideal model of the static sagittal cervical spine. Spine, 1996, 21: 667–675.

2) Gong WT, Hwang Bo G, Lee YM: The effects of Gong’s Mobilization on cervical lordosis, forward head posture, and cervical ROM in abnormal pos-ture of the cervical spine of college students. J Phys Ther Sci, 2011, 23: 531–534.

3) Borden AG, Rechtman AM, Gershon-Cohen J. The normal cervical lordosis. Radiology. 1960; 74:806–9.

4) Lippa L, Lippa L, Cacciola F. Loss of cervical lordo-sis: what is the prognosis? J Craniovertebral Junction Spine. 2017;8(1):9–14.


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Invention of Clinical ThermometerHistory

Bhupendra Chaudhary1

1. Senior Consultant Neurologist Director and Head, Deptt. of Neurosciences, Jaswant Rai Speciality Hospital, Meerut (U.P.) E-mail: [email protected]

IntroductionOf the many tools and instruments regarded as essential to the clinical examination, none has had such widespread application as the clinical thermometer. In the time of Hippocrates, only the hand was used to detect the heat or cold of the human body, although fever and chills were known as signs of morbid processes. In Alexandrine medicine, the pulse was observed as an index of disease, superseding the crude assessment of temperature. Hero of Alexandria (10-70 AD) knew of the principle that certain substances, notably air, expand and contract and described a demonstration in which a closed tube partially filled with air had its end in a container of water.1 The expansion and contraction of the air caused the position of the water/air interface to move along the tube.

Such a mechanism was later used to show the hotness and coldness of the air with a tube in which the water level is controlled by the expansion and contraction of the gas. These devices were developed by several European scientists in the 16th and 17th centuries, notably Galileo Galilei.2 As a result, devices were shown to produce this effect reliably, and the term thermoscope was adopted because it reflected the changes in sensible heat (the concept of temperature was yet to arise). The difference between thermoscope and a thermometer is that the latter has a scale. Though Galileo is often said to be the inventor of the thermometer, what he produced were thermoscopes.

A large step forward was achieved by Santorio (Sanctorio Sanctorius) who invented a mouth thermometer. Santorio (1561–1636) was an Italian physiologist, professor at Padua. He made quantitative experiments in temperature, respiration, and weight, and measured ‘insensible perspiration’ that laid the foundation for the study of metabolism. Sanctorio

Sanctorius produced several designs, but all were cumbersome and required a long time to measure the oral temperature. To this day, the time to get an accurate, stable reading remains difficult. Glass thermometers must remain in contact with sublingual tissue for 8 min. Rectal temperature takes 5 min, axillary temperatures up to 11 min.3

In 1665, Christiaan Huygens added a scale extending from the freezing point to the boiling point of water, the

Daniel Gabriel Fahrenheit

Anders Celsius

Fahrenheit’s Thermometer

Celsius Thermometer


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original centigrade system. Gabriel Daniel Fahrenheit based his new scale on a mixture of ice and ammonium chloride as the lower point. He found mercury more useful than water, as it expanded and contracted more rapidly.

In 1714 Dutch scientist and inventor Daniel Gabbiel Fahrenheit invented the first reliable thermometer, using mercury instead of alcohol and water mixtures. In 1724 he proposed a temperature scale which now (slightly adjusted) bears his name. He could do this because he manufactured thermometers, using mercury (which has a high coefficient of expansion) for the first time and the quality of his production could provide a finer scale and greater reproducibility, leading to its general adoption. In 1742, Anders Celsius (1701-1744) proposed a scale with zero at the boiling point and 100 degrees at the freezing point of water,4 though the scale which now bears his name has them the other way around. French entomologist Rene Antoine Ferchault de Reaumur invented an alcohol thermometer and temperature scale in 1730 that ultimately proved to be less reliable than Fahrenheit’s mercury thermometer.

The first physician that put thermometer measurements to clinical practice was Herman Boerhaave (1668-1738). In 1866, Sir Thomas Clifford Allbutt (1836-1925) invented a clinical thermometer that produced a body temperature reading in five minutes as opposed to twenty.

In 1868, Carl Wunderlich published temperature recordings from over 1 million readings in over 25000 patients made with a foot-long thermometer used in the axilla. He established a range of normal temperature from 36.3 to 37.5 °C. Temperatures outside this range suggested disease. The size of thermometers remained a major disadvantage. Aitkin in 1852 made a mercury instrument with a narrower tube sited above a bulb

reservoir; this ensured that the mercury did not drop back after the reading had been taken. It was left to Thomas Clifford Allbutt (1836–1925) to design in 1866 a conveniently portable 6-inch clinical thermometer, able to record a temperature in 5 min. It replaced a foot-long model, which required 20 minutes to determine a patient’s temperature. The measurement of temperature soon became an inescapable routine.5

In 1999, Dr. Francesso Pompei of the Exergen Corporation introduced the world’s first temporal artery thermometer, a non-invasive temperature sensor which scans the forehead in about two seconds and provides a medically accurate body temperature.6

Recent advances in thermometer design include digital, electronic direct and predictive, infra-red ear thermometers, and dot-matrix or phase-change thermometers.

REFERENCES1. T.D. McGee (1988) Principles and Methods

of Temperature Measurement ISBN 0-471-62767-4.2. R.S. Doak (2005) Galileo; astronomer and physicist

ISBN 0-7565-0813-4 p36.3. Santorio S. In: Commentaria in Primam Fen Primam

Libri Canonis Avicenna. 1625. Cited and illustrated by Lyons AS, Petrucelli RJ. Medicine: An Illustrated History. New York, Abrams, 1987:437

4. R.P. Benedict (1984) Fundamentals of Temperature, Pressure and Flow Measurements, 3rd ed, ISBN 0-471-89383-8 page 6.

5. Sir Thomas Clifford Allbutt (http://www.britannica.com/EBchched/topic/16002/Sir-Thomas-Clifford-Allbutt), Encyclopaedia Britannica.

6. Exergen Corporation (http://www.exrgen.com/about.htm). Exergen.com. Retrieved on 2011- 03-30.


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The Editorial Process The manuscripts will be reviewed for possible publication with the understanding that they are being submitted to one journal at a time and have not been published, simultaneously submitted or already accepted for publication elsewhere. The Editors review all submitted manuscripts initially. Manuscripts with insufficient originality, serious scientific flaws or absence of importance of message are rejected. The journal will not return the unaccepted manuscripts. Other manuscripts are sent to two or more expert reviewers without revealing the identity of the contributors to the reviewers. Within a period of 8 to 10 weeks, the contributors will be informed about the reviewers’ comments and acceptance/rejection of manuscript.

Articles accepted would be copy edited for grammar, punctuation, print style and format.

Types of Manuscripts and word limitsOriginal articles: Randomized controlled trials, intervention studies, studies of screening and diagnostic test, outcome studies, cost effectiveness analyses, case-control series, and surveys with high response rate. Up to 2500 words excluding reference and abstract.

Review articles: Systemic critical assessments of literature and data sources. Up to 3000 words excluding reference and abstract.

Case reports: New/interesting/very rare cases can be reported. Cases with clinical significance or implications will be given priority, whereas, mere reporting of a rare case may not be considered. Up to 1000 words excluding reference and abstract and up to 10 references.

Short reports: These are usually short technical reports about a procedure or technique that is unique or new or in the experience of the author of interest to the readers.

Letter to the Editor: New/interesting/very rare cases with clinical significance. Up to 600 words excluding reference and abstract and up to 5 references.

Letter to the Editor: Should be short, decisive observation. They should not be preliminary observations that need a later paper for validation. Up to 400 words and 4 references.

Neuro Image: Classical clinical/radiological/pathological image up to 250 words and 4 references.

Announcements of conferences, meetings, courses, awards, and other items likely to be of interest to the readers should be submitted with the name and address of the person from whom additional information can be obtained. Up to 100 words.

Limits for number of images and tables: for all the above-mentioned categories the number of image and table should not be more than one per 500 words.

Manuscript Preparation GuidelinesArticles submitted to Journal of Internal Medicine of India-UP should conform to the guidelines indicated below. Before you submit, please study the author checklist provided at the end of this document. Following is the chronological order of topics to be included in the article:

Title, Abstract, Keywords, Introduction, Concept headings (include statistical methodology, if any) Discussion, Conclusion, Acknowledgements (If any), References

Cover LetterThe covering letter should be written by the corresponding author indicating how the manuscript is suitable for publication in Journal of Internal Medicine of India. All authors names are to be included in the letter (preferably along with their signatures) stating the article has not been published elsewhere or communicated to any other publication apart Journal of Internal Medicine of India. If the article is authored by a student, it is requested that he/she obtain the approval of the institution department prior to submitting the article.

Electronic FormatsAuthors are requested to send their articles in MS Word (.doc) format. In case of any difficulty with the manuscript submission process or concern regarding the suitability of your files, please contact us at [email protected] , or [email protected]

Article TitleThe title should be concise and specific to the topic of the article Avoid using abbreviations in the title. Titles should be presented in title case, meaning that all words except for prepositions, articles, and conjunctions should be capitalized. All botanical names should be in italics.

Manuscript


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E.g. An Experimental Study of Classification Algorithms for Crime Prediction

Author names & AffiliationsProvide first names or initials (if used), middle names or initials (if used), and surnames for all authors. Affiliation details should include—department, university or organization, city, state and country for all authors. One of the authors should be designated as the corresponding author with asterisk (*) against his/her name. Only the corresponding author’s email address should be provided in the article. It is the corresponding author’s responsibility to ensure that the author list and the summary of the author contributions to the study are accurate and complete.

Abstract & KeywordsThe abstract introduces the article and should not exceed 300 words. It should mention the techniques used without going into methodological detail and should summarize the most important results. Please do not include any citations in the abstract and avoid using abbreviations if possible.

Authors should provide 4-6 keywords for indexing purposes. Keywords should be written in title case and separated by comma. Avoid general and plural terms and multiple concepts (avoid, for example, ‘and’, ‘of’).

HeadingsFor a better understanding of the content in the article, we encourage authors to number the article headings in Arabic style format. Headings should follow title case, meaning that all words except for prepositions, articles, and conjunctions should be capitalized. All botanical names should be in italics.

For example:

1. Finite Element Modelling (FEM)

1.1 Model Description

AbbreviationsAll abbreviations should be defined on first use in the text along with the abbreviation in parenthesis. E.g. Magnetic Resonance Imaging (MRI)

Units and SymbolsSymbols should be used while referring to alpha, beta, mu, etc (Ex: α, β, µ, etc). All units to follow the International System of Units (SI units).

Figures: General guidelines

Figures Format & Resolution: Authors are requested to supply high-resolution versions of the figures in TIFF, JPEG or EPS format. We require that figures be created at a minimum resolution of 300 ppi.

File size: The file sizes should not exceed 20 MB.

File naming: Naming of figure files should be simple indicating the serial number and last name of author. E.g. if author’s name is Bob Marley, Figure 1 should be named as “Fig 1_Marley”.

Figure submission: Figures should be submitted after uploading the article (in step 4 of the submission process in supplementary files). In case of multiple files, upload the figures in order. E.g. Figure 1 should be uploaded first followed by Figure 2, 3 and so on.

Citation: All figures must be cited in the text and authors should indicate where they are to be inserted in the text. E.g. <insert figure 1 here>.

Figure captions: These have to be included in the text and provided sequentially at the end of the article. The captions should be short having 10-15 words in sentence case style. E.g. Figure 1. Percentage of detection rate vs. number of nodes.

Permissions: Authors should obtain permission from authors for copyright figures and tables before submitting to Journal of Internal Medicine of India.

All figures will be published under a Creative Commons Attribution License, which allows them to be freely used, distributed, and built upon as long as proper attribution is given. Please do not submit any figures that have been previously copyrighted unless you have express written permission from the copyright holder to publish under the CCAL license.

Tables: General guidelines

Tables should be included in the text file at the end of the article.

All tables should have a concise title and written as Table 1 with a period (.).

E.g. Table 1. Stimulation settings

Footnotes can be used to explain abbreviations. Tables extending beyond 1 page should be avoided.

AcknowledgmentsPeople who contributed to the work but do not fit the criteria for authors should be listed in the Acknowledgments,


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along with their contributions. Authors are requested to ensure that anyone named in the Acknowledgments agrees to being so named.

ReferencesOnly published or accepted manuscripts should be included in the reference list. Meetings, abstracts, conference talks, or papers that have been submitted but not yet accepted should not be cited.

In text citations: References cited in text should conform to the Vancouver style. Please refer the Vancouver Style of Referencing.

Reference List: This should only contain references to those works which you have cited in your text. It should appear at the end of your text. It should be arranged numerically by citation number. Examples are indicated below.

Overview of the Production ProcessUpon acceptance of the paper, authors will be contacted by the production team of Journal of Internal Medicine of India. The manuscript will be processed through editing and scrutinized for any missing elements or disparities. Authors will be contacted by the production team and

asked to supply the missing information in their paper. This will be the final stage for authors to send amendments to the manuscript. Upon finalization of the edited files, the files will be processed through typesetting to generate first proofs. Authors will receive the first proofs of their article to resolve any pending queries. Authors are advised not to send any corrections at the proofs stage and are requested to co-operate with the production team to ensure smooth workflow and timely publication of the journal issue.

Author Checklist before SubmissionAre you ready to submit your article? We recommend you check these items one final time before uploading the article on our website. In case of any difficulty in submitting your article, please get in touch with us at [email protected]

• Cover letter with all author names

• Manuscript is adhering to guidelines

• All author affiliations provided

• Corresponding author’s email address provided

• All figures and tables are called out in the manuscript

• All figures have been uploaded on the online submission platform


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56 © JIMI • AUG. - OCT. 2018 • VOL. 12

API-UP CHAPTERMEMBERSHIP FORM

To,Honorary SecretaryAssociation of Physician of India ( U.P. Chapter),C-403, Nirala Nagar, Lucknow 226020.

We hereby propose the admission ofName (in full & block letters) :

_____________________Gender M F

Qualification : ________________________________________________________________________________________

( Mention the discipline in which postgraduate qualification obtained)

Institution/University : __________________________________________________________________________________

Year of Obtaining first postgraduate qualification : ___________________________________________________ ________

API Member (Yes / No), If yes Membership No. _____________________________________________________________

Mailing Address : _____________________________________________________________________________________

____________________________________________________________________________________________________

Contact No. : ___________________________E mail: ______________________________________________________

Permanent Address : ___________________________________________________________________________________

____________________________________________ ________________________________________________________

Applied for: (Please appropriate after reading the conditions overleaf)

Life Member(LM) Associate Member(AM) Provisional Associate Member (PAM)

(For PG Students)

To the best of our knowledge and belief, the above particulars are correct and we consider him/her a fit and proper person tobe admitted as a member of the association.

_______________________ ___________________________Signature of Proposer Signature of Seconder

Name _______________________________ Name ___________________________________

API Membership No. __________________ API Membership No. ______________________

UP API Membership No. _______________ UP API Membership No. ___________________

Life membership Subscription (Inclusive of Admission Fee) Rs. 4000/- (Rupees Four thousand only) is herewith enclosedvide Bank Draft No. __________________ Dated ____________ in Favor API- Payable at Lucknow.

Subject to approval of the Governing Body in a Special Meeting, I agree to become a member and if admitted, to abide by theRules and Regulations of the Association.

_______________________Signature of Candidate

For Office Use

Admitted / Not Admitted Vide Governing Body Meeting Dated : _______________held at ___________________

Payment received Rs. ________________ Vide Bank Draft No._________________dated___________________

drawn on ___________________________________Bank.

Membership No. L/AM/PAM _______________

Photograph

Photocopy of registration with UP Medical Council of India or the Central Medical Council of

India.

Photocopy of the postgraduate qualification.

There are two categories of membership:

Any person who is a member of Central body of Association of Physicians of

India and is residing in Uttar Pradesh of India is eligible to become life member of U.P.Chapter.Central API membership is permissible to those who hold a postgraduate degree M.D or D.M. or itsequivalent in Internal Medicine from any institution or University recognised by the Medical Councilof India or approved by the Governing body of the Association of Physicians of India provided he/sheis not engaged in general or dispensing practice. Internal Medicine includes specialities such asCardiology, Gastroenterology, Diabetology, Nephrology, Neurology, Clinical Hematology, Chest,Immunology, Rheumatology, Medical Oncology, Psychiatry, Pediatric Medicine, Dermatology,Radiation Medicine, Ultrasonography and others approved by Governing Body.

:- There are three categories of Associate Life Member:

I. Those who are eligible to become Ordinary or Life member of Central body of API but have notbecome so far.

II. Any person holding a postgraduate degree or diploma recognized by Medical Council of India inany branch of Medical Science but is not eligible to become life member is eligible to becomeAssociate Life Member.

III. Provisional Associate Member: A Postgraduate student in Medicine may be enrolled asfull membership fees of the chapter. Such

Membership will ordinarily last for five years unless the member informs about completion ofpostgraduate courses. In such cases he/she will be considered for Life Member/Associate LifeMembers as per fulfillment of the requirement.

Note:

Associate Life Member shall not have right to vote, propose, second or contest any position of thegoverning body. They shall also not be entitled for participation, except when stated otherwise, in

recommendation for any distinction conferred by the U.P. Chapter.

Photocopy of this form can also be used.


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58 © JIMI • AUG. - OCT. 2018 • VOL. 12

Thanks & RegardsEditor-in-Chief UP JIMI

Dr. S. ChakravortyMob: 9810210479, 9667668146

Email: [email protected], [email protected]

Journal of Internal Medicine of India (Uttar Pradesh)

NOTES

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