Analytica MedicaISSN:0974-4142

Volume :16 No: 1 & 2 Jan- Dec 2013

Journal of Scientifi c & Research Society

BLDE UniversityShri B. M. Patil Medical College

Hospital & Research Centre,Bijapur-586 103, Karnataka, India

Analytica MedicaISSN:0974-4142

Volume : 16 No. 1 & 2 Jan-Dec. 2013

Journal of Scientific & Research Society

BLDE UniversityBijapur-586 103, Karnataka, India

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ISSN:0974-4142Analytica MedicaAn

alytica

Medic

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Disclaimer:Statements and opinions expressed in the articles published in the journal are those of authors and not necessarily of the Editor. Neither the Editor nor the Publisher guarantees, warrants or

endorses any product or service advertised in the journal.Published by: Scientific & Research Society

BLDE University, Bijapur-586 103, Karnataka, INDIAPrinted by:BLDEA Offset Printers, Bijapur

Volume: 16 No : 1& 2 Jan- Dec-2013

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Honorary Editor in Chief Dr M. S. Biradar Dean, Faculty of Medicine & PrincipalEditor in Chief Dr S. P. Chaukimath Professor & Head, Dept. of PsychaitryEditors Dr Arun Patil KIMS, Karaad Dr Sharan Badiger Dr Aparna Palit Dr Manpreeth Kour Dr Shailaja PatilAssistant Editors Dr Nilima Dongre Dr Satish PatilEditorial Board Dr. S. D. Desai Dr. Manjunath Aithal HOD, Anatomy HOD, Physiology Dr. D. B. Rathi Dr. B. R. Yelikar HOD, Biochemistry HOD, Pathology Dr. P. K. Parandekar Dr. D. I. Ingale HOD, Microbiology HOD, Forensic Medicine Dr. R. S. Wali Dr. M. M. Angadi HOD, Pharmacology HOD, Community Medicine Dr. N. H. Kulkarni Dr. Vallabha K. HOD, ENT HOD, Ophthalmology Dr. M. S. Mulimani Dr. Tejaswini Vallabha HOD, Medicine HOD, Surgery Dr. P. B. Jaju Dr. S. V. Patil HOD, OBGY HOD, Paediatrics Dr. O. B. Pattanashetty Dr. A. C. Inamdar HOD, Orthopaedics HOD, Dermatology Dr. M. M. Patil Dr. R. S. Babar HOD, Radiology HOD, Pulmonology Dr. S. B. Patil HOD, Urology

Original ArticlesHYPOGLYCEMIC ACTIVITY OF SOME CURCUMIN ANALOGUE SYNTHETIC COMPOUNDS IN ALLOXAN-INDUCED DIABETIC RATSKusal K. Das, Swati N. Tikare, Roberto Di Santo, Roberta Costi,Antonella Messore, Luca Pescatori, Giuliana Cuzzucoli Crucitti, Jameel G. Jargar, Shaheen H. Hattiwale, Salim A. Dhundasi and Luciano Saso .....................................................................1PROCALCITONIN AS A MARKER OF NEONATAL SEPSISNazeerahmed, Shruti S, A.S.Akki, S.V.Patil ........................................................................................8

LOW DENSITY LIPOPROTEIN/HIGH DENSITY LIPOPROTEN RATIO A BETTER PREDICTOR OF DYSLIPIDEMIA IN SUBCLINICAL HYPOTHYROIDISMSmita Kottagi, Dileep Rathi, Nilima Dongre ................................................................................. 13

Case ReportTRANSFUSION RELATED ACUTE LUNG INJURYL.S.Patil, S.G.Balaganur, Amith Gupta.B.A ............................................................................20

CHRONIC DIARRHOEA AS A PRESENTATION OF CRONKHITE - CANADA SYNDROME, A RARE NONINHERITED GASTROINTESTINAL POLYPOSIS - A CASE REPORTNadagouda S.B., Biradar M.S., .........................................................................................................22

TUBO OVARIAN COMPLICATIONS FOLLOWING HYSTERECTOMY- A CASE REPORTJaju Purushottam B, Ashwini V, S.R.Bidri, Jayashree Sajjanar, Sangamesh M. .......................26

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME: A CASE REPORTSharan Badiger, Mudanur S.R., Deepak Kadeli, Bhairavi Joshi. .................................................30

DEATH SEAT - A CASE REPORTGannur Dayanand G, Nuchhi U C, Yoganarasimha k .............................................................33MEDIAL EDUCATIONCONSTRUCTING MULTIPLE CHOICE QUESTIONS (MCQ)Surekha B. Hippargi. ...........................................................................................................................36

Analytica MedicaJan-Dec 2013 CONTENTS Volume. 16 Number. 1& 2

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1

ORIGINAL ARTICLE

HYPOGLYCEMIC ACTIVITY OF SOME CURCUMIN ANALOGUE SYNTHETIC COMPOUNDS IN ALLOXAN-INDUCED DIABETIC

RATSKusal K. Das1,2, Swati N. Tikare2, Roberto Di Santo3, Roberta Costi3, Antonella Messore3, Luca Pescatori3, Giuliana Cuzzucoli Crucitti3, Jameel G. Jargar2, Shaheen H. Hattiwale2,

Salim A. Dhundasi2 and Luciano Saso4 1Department of Physiology, BLDE’s Shri B.M.Patil Medical College, Bijapur586103,Karnataka,India

2Environmental Health Research Unit, Department of Physiology, Al Ameen Medical College, Bijapur-586108, Karnataka, India,

3Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Italy.4Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome,

P.le Aldo Moro,5-00185 Rome, Italy,

ABSTRACT:The currently available therapies for type 2 diabetes have been unable to achieve normoglycemic

status in majority of the patients due to limitations of the drug itself or its side effects. So in our effort to develop potent and safe oral anti diabetic agents we evaluated the hypoglycemic actions of ten synthetically prepared curcumin analogue polyphenol compounds, in vitro and in vivo system on alloxan induced male diabetic albino rats. In vitro studies showed compound (4) 7-Bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione to be the most potential hypoglycemic agent followed by compound (10) 1,5-Bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one . Further oral glucose tolerance test with compound (4), compound (10) and reference hypoglycemic drug Glipizide showed that the reduction in blood glucose levels at the end of 2hrs in case of compound (4) was almost near to reference drug. Thus we found compound (4) to be a potential hypoglycemic agent which reduces glucose concentration both in vitro and in vivo.KEYWORDS : Curcumin analogue synthetic compounds, hypoglycemic action, OGTT, diabetic rats

INTRODUCTION:Currently available treatments for type 2 diabetes include insulin and various oral antidiabetic

agents such as sulfonylureas, biguanides, glucosidase inhibitors. Many of these oral antidiabetic agents have a number of serious adverse effects. There is a growing interest in herbal remedies because of their effectiveness, minimal side effects in clinical experience and relatively low costs. Herbal drugs or their extracts are prescribed widely, even when their biological active compounds are unknown. Even the World Health Organization (WHO) approves the use of plant drugs for different diseases, including diabetes mellitus 1. It is well established that diabetes is associated with low level of antioxidants and many plants show hypoglycemic property due to their antioxidant potential 2. Many compounds used in medicine to treat diabetes are either derived directly from plants or as a synthesized form. It is also known that many of the synthetic products like polyphenols are based on natural product3.Curcumin is a member of the linear diarylheptanoid class of natural products in which two oxy-substituted aryl moieties are linked together through a seven-carbon chain. The curcumin

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analogues are classified in three groups: analogues from turmeric, analogues from Mother Nature, and synthetic analogues 4. Most of the analogues of curcumin are not obtained from curcumin but rather have been synthesized from smaller synthons. Curcumins are usually assembled from araldehydes and acetylacetone, and this route enables synthesis of a diverse set of curcumin analogues starting from araldehydes. The curcumin derivatives are generally synthesized by derivatization, starting from curcumin. For example, the phenolic hydroxy group may be acylated, alkylated, glycosylated, and amino acylated 5,6. The antioxidant activities of curcumin and related compounds have been investigated by a variety of assay systems, in both in vitro and in vivo conditions 4. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin 7.

Various reports are available on curcumin and its natural and synthetics analogues as anticancer, anti-tumor, anti-arthritic, antiseptic, antibacterial, anti-inflammatory and also its antidiabetic property. Recently a few studies have confirmed its antidiabetic and hypoglycemic property and also proposed the underlying molecular mechanisms8. Diverse curcumin analogue compounds were used in these studies. So in our study we aimed to assess hypoglycemic and antidiabetic activities of ten curcumin analogue derivatives which were synthetically prepared, and followed up to find the most promising compound among them.

Table 1: Characteristics of key curcumin analogue synthetic compounds

Code No. of key

compounds.Compound

Known hypoglycemic

compound.

Analogues known as

hypoglycemic compound

λmax in nm

Comp 41,7-bis(3,4-dimethoxyphenyl)hepta-1,6-

diene-3,5-dione

Yes18 Yes19 463.0

Comp 101,5-bis(4-hydroxy-3-methoxyphenyl)penta-

1,4-dien-3-one

Yes16 Yes16 432.0

Word Style “FE_Table_Footnote” Footnote: Peak wavelength (λmax), nanometer (nm)METHODS:The following were the curcumin analogue compounds synthesized to study the anti diabetic

action.

OH

OCH3

HO

H3COO

O O

OCH3H3CO

H3CO OCH3

3

Comp 1: 1-Ethyl-3,5-bis(4-hydroxy-3-nitrobenzylidene)-4-oxopiperidinium chloride (mol.weight461.86), comp 2: 2-Thioxo-5(3,4,5 trihydroxybenzylidene) dihydropyrimidine-4,6(1H,5H)-dione (mol weight 280.25) Comp 3: 1,7-Bis(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (mol.weight 308.32), comp 4: 1,7-Bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione (mol.weight 396.44), comp 5: 1,7-Bis(3,4-dihydroxyphenyl)hepta-1,6-diene-3,5-dione (mol. weight 340.22), comp 6: 1,1’-(1,3-Phenylene) bis[3-(4-hydroxyphenyl)prop-2-en-1-one] (mol. weight 370.38), comp 7: 2,3-Bis(3,4-dihydroxyphenyl)acrylic acid (mol.weight 288.26), comp 8: 2,6-Bis(4-hydroxy-3- methoxybenzylidene) cyclohexanone (mol. weight 366.41), comp 9: 3,5-Bis(3,4-dihydroxybenzylidene)piperidin-4-one hydrochloride (mol. weight 375.80) and comp10: 1,5-Bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (mol.weight 326.35).

The compounds 1-6 and 8-10 (4 and 10 depicted in Table 1, others in Table S1 in supporting information) were synthesized according to the literature9,10. Compound 7 was synthesized following a well known procedure reported in literature11. The 3,4-dihydroxybenzaldehide was condensed with 3,4-dihydroxyphenylacetic acid in presence of acetic anhydride and (Et)3N. In vitro tests can play an important role in the evaluation of antidiabetic herbs or compound as initial screening tool which may be further followed up to human or animal research. We did in vitro test and in vivo studies on alloxan induced diabetic male rats

The hypoglycemic effect of the curcumin analogue synthetic compounds in vitro was done by using glucose oxidase-peroxidase method by determining the percentage reduction of glucose concentration. The results showed that at pH 6.5 among the ten synthetic compounds evaluated a noticeable reduction in glucose concentration were found in comp 3, comp 4, comp 5, comp 8 and comp 10 (Table-2). It was also observed that the degree of hypoglycemic effect of the compounds was variable with change in glucose concentration in the samples. Comp 4 was found to be the most potential hypoglycemic compound followed by comp 10. The results indicate the presence of active constituents in the solvents extracted from the compounds material. Perhaps enolic form of heptadienone or pentadienone of these synthesized compounds may act as an electron donor which is very common mechanism for the scavenging activity of phenolic antioxidant to alter characteristics of glucose molecules12. The hypoglycemic actions of these compounds also corroborate with previous findings on these analogue compounds13-17.

We further evaluated these two promising compounds (comp 10 & comp 4) by in vivo studies on alloxan induced diabetic rats by Oral glucose tolerance test (OGTT). OGTT for rats were performed according to the standard method (Du Vigneaud and Karr, 1925). Group I served as untreated control and the oral 2-h glucose tolerance test (OGTT) was carried out by estimating glucose of

Table-2: In-vitro hypoglycemic effect of some Curcumin analogue synthetic compounds

Code No. of compounds In vitro glucose concentrations (mg/dL)20 40 60 80 100

Comp 1 16.8% 8.65% 5.73% 4.11% 3.5%Comp 2 -- 8.57% 4.6% -- --Comp 3 67.85% 36.92% 37.11% 19.18% 17.22%

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Comp 4* 93.35% 75.20% 58.90% 50.80% 50.97%Comp 5 44.45% 35.62% 44.45% 44.83% 38.71%Comp 6 14.30% 13.35% -- 1.41% 1.69%Comp 7 -- 7.5% -- -- --Comp 8 52.00% 85.00% 66.60% 51.75% 48.00%Comp 9 18.20% 18.20% 12.50% -- --

Comp 10* 76.65% 81.4% 51.11% 38.46% 27.82%Values indicate the percentage reduction in glucose concentration after adding the curcumin

compounds. Glucose estimated by glucose oxidase-peroxidase method at pH 6.5 at different glucose concentrations. * indicates compounds showing significant hypoglycemic actions in vitro. Compounds are named in the text..

Table 3. oral Glucose tolerance test on alloxan induced diabetic rats after treatment with curcumin analogues and Glipizide

Treatment Groups Time after glucose ingestion (h)0 (FBS) 0.5 1.0 1.5 2.0

I(control) 84.62± 2.54a 124.50±15.33b

(+47.1%)95.00± 10.43a

(+12.3%)88..32 ±4.37a

(+4.4%)85.50±4.51a

(+1.0%)II(diabetic) 180.66±15.65a 298.50 ±26.57b

(+65.2%)351.00 ±34.86c

(+94.3%)410.65± 25.45d

(+127.3%)410.34±43.54d

(+127.13%)

IIIdiabetic+ comp 10) 175.66±13.26a 276.33±25.43b

(+57.3%)300.45.±19.61c

(+71.04%)280.16 ±7.39b

(+59.48%)280.45±33.06b

(+59.65%)

IV (+diabetic + comp 4) 184.4± 20.64a 222.34±17.54b

(+20.5%)186.00± 32.45a

(+0.8%)133.50±11.70 c

(-27.6%)102.45±10.45d

(-44.5%)V(dibetic + glipizide) 187.50±14.18a 216.66+12.75b

(+15.6%)185.00±11.41a

(-1.8%)125.66 ± 9.00c

(-32.9%)89.00± 4.49d

(-52.5%)

F=54.598 P= 0.0000

F= 66.25 P= 0.000

F=108.36 P= 0.000

F=582.21 P= 0.000

F= 204.21 P= 0.000

F.B.S.; fasting blood sugar. Horizontal values are the mean + SD of six observations in each group in every 0.5h interval till 2.0h. In each row, values with different superscripts (a, b, c, d) are significantly different from each other (p < .05). One way ANOVA of different groups in every 0.5h interval till 2.0h is referred below vertically. Horizontal rows also indicate percent change of glucose concentrations in each 0.5h interval till 2.0h from baseline FBS (0). comp 4: 1,7-Bis(3,4 dimethoxyphenyl) hepta-1,6-diene-3,5-dione, comp 10 1,5-Bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one , and glipizide blood sample from tail vein by using glucometer (Accu-chek active,

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Roche diagnostics, Germany) at 0, 30, 60, 90 and 120 minutes. An oral glucose load of 0.35g/100g body weight was administered for the test18. Group II rats were diabetic control and similar OGTT was conducted on these animals. Group III diabetic rats were administered RDS 1203 orally at a dose of 100µg.kg-1 body weight followed by OGTT. Group IV diabetic rats were administered RDS 1212 orally at a dose of 100µg/kg b.wt. followed by OGTT. Group V diabetic rats received a dose of 2.5mg.kg−1 of a known antidiabetic drug Glipizide, as reference drug19.

All the experimental procedures followed were performed in accordance with the approval of the Institutional Animal Ethics Committee (1169/ac/08/CPCSEA) under strict compliance of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines for the experimental studies.

RESULTS & DISCUSSION:The results of OGT test are depicted in Table 3. We found that that aqueous extract of 1,7-Bis(3,4-

dimethoxyphenyl)hepta-1,6-diene-3,5-dione (comp 4) reduces the high blood glucose levels of diabetic rats during the oral glucose tolerance test. Glipizide was used as reference drug in diabetic models for positive control.

Percent change observation of this OGTT study reveals that blood glucose level of group I (untreated control), group IV (alloxan diabetic + comp 4) and group V (alloxan diabetic + glipizide) rats reach its peak at 0.5h from FBS level followed by reduction of blood glucose levels till 2.0h. In case of group II (alloxan diabetic) and III (alloxan diabetic + comp 10) the peak level of blood glucose were noticed at 1.5h and 1.0h respectively and here onwards till 2h the levels of blood glucose steadily declined. This indicates that it takes about 1 h for the active ingredient of compound 4 or its metabolites in the water extract to enter into the circulation and reach target tissues to bring about hypoglycaemic effect1.

From this OGTT study it may be noted that comp 4 decreases blood glucose level of alloxan treated diabetic rats by 44.45% at the end of 2.0h from its baseline FBS level. This percent change reduction of comp 4 is near reference hypoglycemic drug i.e. glipizide (52.53% reduction from baseline FBSlevel).

It is interesting to note that the synthetic polyphenol compound 1,7-Bis(3,4-dimethoxyphenyl) hepta-1,6-diene-3,5-dione ( comp 4) was nearly equal effective as reference drug. It is likely to expect that the aqueous solution of 1,7-Bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione ( comp 4) has some direct effect by increasing the tissue utilization of glucose20, by inhibiting hepatic gluconeogenesis or absorption of glucose into the muscles and adipose tissues21. The elevated blood glucose levels in the diabetic animals used by us were in the range of 150–190 mg/dl, which resembles type-II diabetes (150 to about 250 mg/dL) with partially functional pancreas. From our OGTT results it can also be interpreted that comp 4 might enhance insulin release from partially functional pancreatic beta cells by the release of insulin stored in the granules.

The findings of this study also suggest that this compound exhibited actions similar to glipizide, that is, stimulation of the surviving beta- cells to release more insulin22. It has been well-documented that most medicinal plants are enriched with phenolic compounds and flavonoids which have excellent antioxidant and antidiabetic properties. In the present experiment on oral glucose tolerance test we have found that only the compound 4 (100 µg/kg) significantly reduced the blood sugar level

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in alloxan treated hyperglycemic rats, where as comp 10 did not show similar type of hypoglycemic responses to OGTT although in vitro studies had shown decrease in glucose concentration.

CONCLUSION:In conclusion, the comp 4 1,7-Bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione a curcumin

analogue compound (100 µg.kg-1) was found to be a potential hypoglycemic agent which reduced glucose concentration in vitro. This finding was further supported with in vivo studies on alloxan-induced diabetic animals. But in case of comp 10 1,5-Bis (4-hydroxy-3-methoxyphenyl) penta-1,4-dien-3-one, another curcumin analogue compound, in vitro effects did not directly correlate with in vivo results. It’s in vitro test was definitely better when compared with oral glucose tolerance of alloxan diabetic rats. Further study is needed to establish exact hypoglycemic mechanism of action, pharmacodynamics, pharmacokinetics, dosage, safety profile etc., of 1,7-Bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione (4), a curcumin analogue synthetic compound in the future.

Corresponding Author* Kusal K. Das, Professor, Department of Physiology, Sri B.M. Patil Medical college, BLDE University, Bangaramma Sajjan Campus, Solapur Road, Bijapur, Karnataka, India.Funding SourcesNone declaredACKNOWLEDGMENT The authors greatly acknowledge Sapienza University of Rome, Italy for their support to carry

out this Indo-Italian Research Project under the supervision of Prof.Luciano Saso and Prof.Kusal K.Das.

REFERENCES1. Gupta, R.K., Kesari, A.N.,Watal, G.,Murthy, P.S.,Chandra, R.,Maithal, K et al. Hypoglycaemic

and antidiabetic effect of aqueous extract of leaves of Annona squamosa(L.) in experimental animal. Current Sci , 2005,88(8),1244-1254

2. McCune, L.M., Johns, T. Antioxidant activity in medicinal plants associated with the symptoms of diabetes mellitus used by the indigenous people of the North American boreal forest. J. Ethnophamacol, 2002, 82,197-205

3. Rubatzky, V.E. World Vegetables. 2nd Edn. International Thomson Publishing, pp.42.,19974. Anand, P., Sherin, G., Thomas, S.G., Kunnumakkara, A.B. , Sundaram, C., Kuzhuvelil, B.,

Harikumar, K.B., Sung, B et al. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem. Pharmacol, 2008,76,1590 – 1611

5. Kumar, S., Dubey, K.K., Tripathi, S,, Fujii, M., Misra, K. Design and synthesis of curcumin-bioconjugates to improve systemic delivery. Nucl. Acids Symp. Ser, 2000,75,6

6. Mishra, S., Kapoor, N., Mubarak, Ali A., Pardhasaradhi, B.V., Kumari, A.L., Khar, A, et al. Differential apoptotic and redox regulatory activities of curcumin and its derivatives. Free Radic. Biol. Med, 2005,38,1353–60.

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7. Ohori, H., Yamakoshi, H., Tomizawa, M., Shibuya, M., Kakudo, Y., Takahashi, A et al. Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer. Mol. Cancer Ther, 2006,5(10),2563–71

8. Takikawa, M., Kurimoto, Y., Tsuda, T., Curcumin stimulates glucagon-like peptide-1 secretion in GLUTag cells via Ca(2+)/calmodulin- dependent kinase II activation. Biochem Biophys Res Commun. 2013 May 31;435(2):165-70. doi: 10.1016/j.bbrc.2013.04.092. Epub 2013 May 6...

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11. Khan, B., Arayne, M.S., Naz, S., Mukhtar, N. Hypoglycemic activity of aqueous extract of some indigenous plants. Pakistan J. Pharmceut. Sci,2005, 18(1),62-64

12. Khan, N.H., nur-E Kamal, M.S.A., Rahman, M. Antibacterial activity of Euphorbia thymifolia Linn. Indian J. Med. Res. 1988, 87, 395-397.

13. Dhandapani, S., Ramasamy, S.V, Rajagopal, S.,Namasivayam, N. Hypolipidemic effect of Cuminum cyminum L. on alloxan-induced diabetic rats. Pharmacol. Res, 2002, 46 (3), 251-255

14. Sridevi, S., Chary, M.G., Krishna, D.R., Diwan PV.Pharmacodynamic Evaluation of transdermal drug delivery system of glibenclamide in rats. Indian J. Pharmacol , 2000, 32, 309 -31

15. El-Hilaly, J., Tahraoui, A., Israili, Z.H., Lyoussi, B.Hypolipidemic effects of acute and sub-chronic administration of an aqueous extract of Ajugaiva L. whole plant in normal and diabetic rats. J. Ethnopharmacol, 2006,105, 441–448.

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19. Sharma, R.A., McLelland, H.R., Hill, K.A., Ireson, C.R., Euden, S.A., Manson, M.M., Pirmohamed, M., Marnett, L.J., Gescher, A.J., Steward, W.P: Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res, 2001, 7(7),1894-1900

20. Du Zhi-Yun; Liu, Rong-Rong; Shao, Wei-Yan; Mao, Xue-Pu; Ma, Lin; Gu, Lian-Quan; Huang, Zhi-Shu; Chan, Albert . α-Glucosidase inhibition of natural curcuminoids and curcumin analogs . Eur. J. Med. Chem., 2006, 41(2), 213-218.

21. Ponnusamy, S., Zinjarde,S., Bhargava, S., P.R., Rajamohanan, P.R. Discovering bisdemethoxycurcumin from curcuma longa rhizome as a potent small molecule inhibitor of human pancreatic α- amylase, a target for type-2 diabetes. Food Chemistry, 2012, 135, 2638-2642.

22. Hu, Te-Yu; Liu, Cheng-Ling; Chyau, Charng-Cherng; Hu, Miao-Lin. Trapping of Methylglyoxal by Curcumin in Cell-Free Systems and in Human Umbilical Vein Endothelial Cells.J. Agr. Food Chem, 2012, 60(33), 8190-8196

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Original Article

PROCALCITONIN AS A MARKER OF NEONATAL SEPSIS

Nazeerahmed, Shruti S, A.S.Akki, S.V.PatilDepartment of Paediatrics

Sri B.M.Patil Medical College, Hospital & Research Centre

ABSTRACTEarly diagnosis of neonatal sepsis and appropriate treatment decreases the mortality and morbidity

of these infants. The aim of this study was to assess the role of procalcitonin (PCT) as a marker in the early diagnosis, treatment and follow-up of neonatal sepsis. Twenty five neonates with clinical (n=5), suspected (n=13) and proven sepsis (n=7) were evaluated. The PCT levels were measured by immunoluminoassay before and on day 5 of treatment. PTC levels of 0.5-2 ng/ml, 2.1-10 ng/ml and >10 ng/ml were considered as weakly positive, positive, and strongly positive, respectively. The sepsis screen tests and cultures of blood or other sterile body fluids in these three groups of infants were recorded. The levels of PCT in proven sepsis group were higher than that in other groups. Strongly positive PCT level was seen in 2 cases of proven sepsis, 5 cases of suspected sepsis and in 1 case of clinical sepsis. PCT levels were dramatically decreased in three groups on day 5 of treatment. The results show that the serum procalcitonin levels seem to be significantly increased in proven sepsis and decrease dramatically in all types of sepsis after appropriate treatment.

Key Words: Neonatal sepsis; Procalcitonin; Marker; Infection; InfancyINTRODUCTIONNeonatal sepsis is one of the major health problems throughout the world; every year an estimated

30 million newborns acquire infection and 1-2 millions of them die1. Since the clinical signs and symptoms of sepsis in neonates are non-specific and associated with high (28-50%) morbidity and mortality, early suspicion and treatment before blood culture confirmation of it is crucial2. An inflammatory marker such as C-reactive protein (CRP) does not reliably differentiate between the systemic inflammatory response and sepsis2,3. Procalcitonin (PCT), a precursor of calcitonin is a 116 amino acid protein secreted by the C cells of thyroid gland in normal situation but its levels may increase during septicemia, meningitis, pneumonia and urinary tract infection 3,4. This marker also is produced by macrophage, and monocyte cells of various organs in severe bacterial infection and sepsis 5,6. The results of recent studies suggest the usefulness of PCT for early diagnosis of neonatal sepsis 7-19, although other investigations have observed lack of accuracy for this marker 20,

21, 22. Since a kit for quantization of PCT is available for rapid quantitative measurement, we carried out this study to evaluate the serum level of PCT on neonatal sepsis in relation to our classification of neonatal sepsis.

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METHODSThis prospective study was conducted on neonates admitted for sepsis work up to newborn

service and neonatal intensive care unit (NICU) at BLDE University’s Shri B M Patil Medical college hospital and research center, Bijapur, Karnataka, India. Sepsis work up including complete blood count (CBC), blood culture, erythrocyte sedimentation rate (ESR), CRP, urine analysis (UA), urine culture (UC), chest X-ray, cerebro spinal fluid (CSF) analysis and culture was performed in all neonates. Three distinct groups were defined; proven sepsis, suspected sepsis and clinical sepsis (table 1).

Exclusion criteria were administration of antibiotic therapy prior to admission, birth asphyxia, aspiration syndromes, laboratory finding suggestive of inborn error of metabolism and congenital anomalies. The sample size was calculated 25 neonates when considering confidence interval 95% power 80% and error in serum PCT estimation of 0.1 nanogram. Before starting the antimicrobial therapy, blood samples (sample 1) for complete blood count, CRP, ESR, PCT and culture were collected. This procedure was repeated at day 5 after treatment with antibiotics (sample 2). CSF, urine, tracheal and gastric aspirate cultures were obtained. Serum PCT level was measured using quantization immuno-luminometry method by lumitest kit (Brahms Diagnostic, Berlin, Germany). In this assay a PCT level of ≥0.5 ng/ml was accepted as pathological. PTC level 0.5-2 ng/ml, 2-10 ng/ml and >10 ng/ml considered as weakly positive, positive, and strongly positive, respectively.

The study protocol was approved by the ethical committee of BLDE Univarsity. Informed parental consent was obtained for all infants. We used SPSS version 15 for statistical analysis. Correlation between variables and statistical differences were analyzed using Fisher exact, ANOVA, Monte Carlo and Wilcoxon tests. P values of <0.05 were considered to be significant.

Table 1: Criteria employed for defining the sepsis scoreGroup І proven sepsis Clinical signs and symptoms plus a positive bacteria culture.Group ІІ suspected sepsis Clinical signs and symptoms with negative bacterial culture but at least with 2 positive screening tests (ESR, CRP, CBC or CXR)Group III clinical sepsis Clinical signs and symptoms with negative bacterial culture and negative screening test.

RESULTSTwenty five neonates were eligible for the study. These neonates are classified into three groups;

proven sepsis (7 neonates), suspected sepsis (13 neonates) and clinical sepsis (5 neonates) according to the study protocol.

The mean gestational age, birth weight and the sex of the patients in these three groups were similar (P-value 0.096). Early onset sepsis was confirmed in 16 (65.8%), late onset sepsis in 6 (23.7%) and nosocomial sepsis in 3 (10.5%) patients. Causative pathogens and site of involvement were as follows: CSF in one patient positive for Escherichia coli, blood culture in five patients positive for Staphylococcus, Escherichia coli and Klebsiella; urine in two neonates for Staphylococcus and Escherichia coli; and culture of the tip of chest tube was positive for Pseudomonas. Table 2 shows the results of sepsis screening tests including PCT in relation to three classified groups of patients.

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In neonates with proven sepsis in spite of negative result for sepsis screening test, the result of PCT was positive. This result was seen also in some patients with clinical sepsis.

Table 3 shows the serum concentrations of PCT in the studied groups. Comparison of serum PCT level before and after treatment reveals significant changes in clinical sepsis (P=0.001) and proven sepsis (P=0.003) groups of patients.

Table 2: Relation between elevated procalcitonin levels with normal sepsis screening tests.Tests Proven Sepsis Suspected Sepsis Clinical Sepsis

N=7 N=13 N=5Normal ESR 5 5 5Normal CRP 4 5 3Normal WBC 6 6 5Normal Chest X-ray 5 8 4Elevated PCT Levels 7 10 3

Table 3: Comparison of serum PCT level before and after treatment.Proven Sepsis

N=7Suspected Sepsis

N=13Clinical Sepsis

N=5Before After Before After Before After

Negative(0.5 ng/ml) 0 5 3 9 2 3Weekly Positive( 0.5-2 ng/ml) 0 2 1 1 0 1Positive( 2-10 ng/ml) 5 0 5 3 2 1Strongly Positive( More than 10 ng/ml) 2 0 4 0 1 0

DISCUSSIONIn the present study the PCT levels were remarkable high in neonates with proven and the levels

dropped dramatically after treatment with antibiotics. Also in some cases of proven and suspected sepsis the levels of PCT were high in spite of negative results for other sepsis screening tests

Previous studies have shown high PCT levels in all neonates with proven or clinically diagnosed various types of neonatal sepsis 8,2,22,24,25. In a recent study Koksal et al concluded that serum procalcitonin level was superior to serum CRP level in terms of early diagnosis of neonatal sepsis, in detecting the severity of the illness and in evaluation of the response to antibiotic treatment 26. In our study the serum PCT level was high in most of the patients before the initiation of therapy, but there was not a significant correlation between the serum PCT level and the type of sepsis. In Koksal study, unlike our study, the level of serum PCT had a significant difference between the four study groups (no sepsis, probable sepsis, highly probable sepsis and possible sepsis). This difference may be due to the small sample size of our study. The serum PCT level in our study decreased significantly in all three sepsis groups which were most evident in proven sepsis group and like the same finding reported in other studies 26, 27, 28.

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Athhan et al in their study revealed that at 7th day of therapy neonates who had achieved clinical recovery had a significant decrease of procalcitonin levels compared to the initial values (P=0.000) 29. This finding was reported also by Viallon and coworkers in 50 patients presenting with bacterial meningitis at day 2 after appropriate antibiotic treatment 30. Carol et al in their study showed that procalcitonin is more sensitive than the CRP in the diagnosis of septicemia, meningitis and urinary tract infection 28.

The usefulness of PCT was assessed by Lopez Sastre and their colleagues as a marker of neonatal sepsis of nosocomial origin in neonates admitted to the 13 neonatology services of 13 acutecare teaching hospitals in Spain over one year. They concluded that serum PCT concentration showed a moderate diagnostic reliability for the detection of nosocomial sepsis from the time of infection 17.

Four of all culture positive neonates in our study had nosocomial sepsis and all of them had elevated PCT levels. One of the limitations of the present study was the shortage of culture positive neonatal standard for sepsis to determine the sensitivity and specifity. For this reason we classified the neonatal sepsis into three groups and assessed the PCT level in relation to the class of sepsis before and after treatment.

CONCLUSIONThe PCT concentration in our study was elevated in culture positive neonates and decreased with

appropriate antibiotic therapy. In some cases of culture positive babies other sepsis screening tests were negative but the level of PCT was elevated. These findings support the usefulness of the PCT to establish an early diagnosis of neonatal sepsis.

ACKNOWLEDGMENTOur institutional review committee of ethical research approved the study. this study was fully

funded by BLDE Univarsity’s Shri B M Patil Medical college hospital and research center, Bijapur, Karnataka, India.

REFERENCES1. Afroza S. Neonatal sepsis-a global problem: an overview. Mymensingh Med J. 2006;15(1):108-

114.2. Andrejaitiene J. The diagnostic value in severe sepsis. Medicina (Kaunas). 2006; 42(1):69

78.3. Carrol CD, Thomson AP. Procalcitonin as a marker of sepsis. Int J Antimicrob Agents.

2002;20(1):1-9.4. Gendrel D, Bohoun C. Procalcitonin as a marker of bacterial infection. Pediatr Infect Dis J.

2000;19(8):679-687.5. Assicot M, Gendrel D, Carsin H, et al. High serum procalcitonin concentrations in patients

with sepsis and infection. Lancet. 1993;341(8844):515-518.6. Dandona P, Nix D, Wilson MF, et al. Procalcitonin increase after endotoxin injection in normal

subjects. J Clin Endocrinol Metab. 1994;79(6):1605-1608.7. Bolmmendahl J, Janas M, Laine S, et al. Comparison of procalcitonin with CRP and differential

white blood cell count for diagnosis of culture–proven neonatal sepsis. Scand J Infect Dis. 2002;34(8): 620-622.

8. Chiesa C, Panero A, Rossi N, et al. Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. Clin Infect Dis. 1998;26(3):664-672.

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9. Chiesa C, Pellegrini G, Panero A, et al. C reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complication, and infection. Clin Chem. 2003;49(1):60-68.

10. Guibourdenche J, Bedu A, Petzold L, et al. Biochemical markers of neonatal sepsis: value of procalcitonin in the emergency setting. Ann Clin Biochem. 2002;39(pt 2):130-135.

11. Joram N, Boscher C, Denizot S, et al. Umbilical cord blood procalcitonin and C reactive protein concentrations as markers for early diagnosis of very early onset neonatal infection. Arch Dis Child Fetal Neonatal ed. 2006;91(1): F65-66.

12. Maire F, Haraud MC, Loriette Y, et al. The value of procalcitonin in neonatal infections. Arch Pediatr. 1999;6(5):503-509.

13. Resch B, Gusenleitner W, Muller WD. Procalcitonin and interleukin-6 in the diagnosis of early–onset sepsis of the neonate. Acta Pediatr. 2003;92(2):243-245.

14. Enguix A, Rey C, Concha A, et al. Comparison of procalcitonin with C reactive protein and serum amyloid for the early diagnosis of bacterial sepsis in critically ill neonates and children. Intensive Care Med. 2001;27(1):211-215.

15. Gendrel D, Assicot M, Raymond J, et al. Procacitonin as a marker for the early diagnosis of neonatal infection. J Pediatr. 1996;128(4):570-573.

16. Vazzalwar R, Pina-Rodrigues E, Puppala BL, et al. Procalcitonin as a screening test for late-onset sepsis in preterm very low birth weight infants. J Peditr. 2005; 25(6):397-402.

17. Lopez Sastre JB, Perez Solis D, Roques Serradilla V, et al. Procalcitonin is not sufficiently reliable to be the sole marker of neonatal sepsis of nosocomial origin. BMC Pediatr. 2006;6:16.

18. Petzold L, Guibourdenche J, Boissinot C, et al. Determination of procalcitonin in the diagnosis of maternal-fetal infections. Ann Biol Clin (Paris). 1998; 56(5):599-602.

19. Perez Solis D, Lopez Sastre JB, Coto Cotallo GD, et al. Procalcitonin for the diagnosis of neonatal sepsis of vertical transmission. An Pediatr (Barc) 2006;64(4):341-348.

20. Franz AR, Kron M, Pohlandt F, et al. Comparison of Procalcitonin with interleukin 8, C-reactive protein and differential white blood cell count for the early diagnosis of bacterial infections in newborn infants. Pediatr Infect Dis J. 1999;18(8):666-671.

21. Koskenvuo MM, Irjala K, Kinnala A, et al. Value of monitoring serum procalcitonin in neonates at risk infection. Eur J Clin Microbial Infect Dis. 2003;22(6):377-378.

22. Lapillonne A, Baddon E, Monneret G, et al. Lack of specificity of procalcitonin for sepsis diagnosis in premature infants. Lancet. 1998;351(9110):121-212.

23. Sachse C, Dressler F, Henkel E. Increased serum procalcitonin in newborn infants without infection. Clin Chem. 1998; 44(6):1343-1344.

24. Monneret G, Labaune JM, Isaac C, et al. Procalcitonin and C-reactive protein level in neonatal infections. Acta Paediatr. 1997;86(2):209-212.

25. Martin-Denavit T, Monneret G, Labaune JM, et al. Usefulness of procalcitonin in neonates at risk for infection. Clin Chem. 1999;45(3):440-441.

26. Koksal N, Harmanci R, Getinkaya M, et al. Role of procalcito-nin and CRP in diagnosis and follow up of neonatal sepsis. Turk J Pediatr. 2007;49(1):21-29.

27. Turner D, Hammerman C, Rudensly B, et al. Procalcitonin in preterm infants during the first few days of life: introducing an age related nomogram. Arch Dis Child Fetal Neonatal Ed. 2006;91(4):283-286.

28. Carol ED, Thomason AP, Hart CA. Procalcitonin as a marker of sepsis. Int J Antimicrob Agents. 2002;20(1):1-9.

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ORIGINAL ARTICLE

LOW DENSITY LIPOPROTEIN/HIGH DENSITY LIPOPROTEN RATIO A BETTER PREDICTOR OF DYSLIPIDEMIA IN

SUBCLINICAL HYPOTHYROIDISM

Smita Kottagi, Dileep Rathi, Nilima DongreDept. of Biochemistry, Shri B. M. Patil Medical College,Hospital & Research Centre, Bijapur.

ABSTRACT:Subclinical hypothyroidism is defined as a serum TSH concentration above the upper limit of

the reference range when serum T3 & T4 concentrations are within reference ranges. Subclinical thyroid disease is a laboratory diagnosis. Patients with subclinical disease have few or no definitive clinical signs or symptoms of thyroid dysfunction. Subclinical hypothyroidism has been associated with higher levels of some cardiovascular risk factors. Despite some conflicting results, many studies found that subjects with subclinical hypothyroidism have higher total cholesterol and low density lipoprotein cholesterol levels than euthyroid subjects. We studied 30 subclinical hypothyroid cases and 30 euthyroid controls. We found the significant increase in the serum levels of TSH (p < 0.001), Total cholesterol (p<0.001), LDL Cholesterol (p<0.001), and LDL/HDL (p<0.001) Systolic blood pressure and diastolic blood pressure (p<0.001). There was no significant change in the levels of serum T3, T4, HDL- Cholesterol. Though established risk factors explain most cardiac risks, significant attention has been focused on alternative biochemical markers to assist in identifying those at risk of a clinical cardiac event. This study underlines the importance of LDL/HDL ratio rather than measurement of individual lipid profile parameters in bringing to light the dyslipidemic state associated with SCH.

Key- words : Subclinical hypothyroidism (SCH) , cardiovascular risk , LDL/HDL ratio , dyslipidemia.

INTRODUCTIONSubclinical hypothyroidism is defined as a serum TSH concentration above the upper limit of

the reference range when serum T4 concentration is within its reference range1.Serum TSH has a log-linear relationship with circulating thyroid hormone levels (a 2-fold change in free thyroxine will produce a 100-fold change in TSH). Therefore, a slight reduction of T4 within the normal range will result in elevation of serum TSH above the normal range. Thus, serum TSH measurement is the necessary test for diagnosis of mild thyroid failure when the peripheral thyroid hormone levels are within normal laboratory range 2. Subclinical thyroid disease is , a laboratory diagnosis. Patients with subclinical disease have few or no definitive clinical signs or symptoms of thyroid dysfunction 1.

Subclinical hypothyroidism or mild thyroid failure is a common problem, with a prevalence of 3% to 8% in the population without known thyroid disease. The clinical importance and therapy for

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mild elevation of serum TSH (<10 mIU/L) 1 and the exact upper limit of normal for the serum TSH level remain subjects of debate4. When the TSH level is above 10 mIU/L, levothyroxine therapy is generally agreed to be appropriate 5. However, management of patients with a serum TSH level of less than 10 mIU/L is controversial.Some authors argue for routine and some for selective therapy6.

Subclinical hypothyroidism has been associated with higher levels of some cardiovascular risk factors. Despite some conflicting results, many studies found that subjects with subclinical hypothyroidism have higher total cholesterol and low density lipoprotein cholesterol levels than euthyroid subjects 7 Mechanisms for the development of hypercholesterolemia in hypothyroidism include decreased fractional clearance of LDL by a reduced number of LDL receptors in the liver in addition to decreased receptor activity. The catabolism of cholesterol into bile is mediated by the enzyme cholesterol 7 –hydroxylase. This liver-specific enzyme is negatively regulated by T3 and may contribute to the decreased catabolism and increased levels of serum cholesterol associated with hypothyroidism. The increased serum lipid levels in subclinical hypothyroidism as well as in overt disease are potentially associated with increased cardiovascular risk. Treatment with thyroid hormone replacement to restore euthyroidism reverses the risk ratio 8.

In hypothyroidism, endothelial dysfunction and impaired vascular smooth muscle relaxation lead to increased superior venacaval resistance .These effects lead to diastolic hypertension in nearly 30% of patients, and thyroid hormone replacement therapy restores endothelial-derived vasorelaxation and blood pressure to normal in most 8.

Subclinical hypothyroidism has been associated with increased risk for atherosclerosis. However, data on coronary heart disease (CHD) in subjects with subclinical hypothyroidism are conflicting7.Although established risk factors explain most cardiac risks, significant attention has been focused on alternative biochemical markers to assist in identifying those at risk of a clinical cardiac event. This study underlines the importance of LDL/HDL ratio rather than measurement of individual lipid profile parameters in bringing to light the dyslipidemic state associated with SCH 9.

METHODSThe study is carried out in the department of biochemistry ,BLDEU’S Shri B M Patil Medical

college Hospital and Research Centre, Bijapur. We studied 30 subclinical hypothyroid cases aged above 35 yrs and 30 age and sex matched euthyroid controls from the general population according to the inclusion and exclusion criteria mentioned below. This study was approved by the Institutional Ethical Committee all the subjects gave an informed consent before undergoing further investigations.

Inclusion criteria: Subclinical hypothyroidism cases having TSH in the range of 4.50 to 14.99 μIU/L, T3 and T4 within normal limits. The euthyroid controls having normal TSH values.

Exclusion criteria: Known hypothyroidism cases, Thyroidectomy cases, Patient with external radiation, previous radioactive iodine therapy, consumption of drugs known to cause SCH, primary or secondary dyslipidemia, Patients with diabetes mellitus, Patients with other systemic illness, renal and hepatic failure cases, were excluded from the study

Venous blood samples were drawn at 8 AM following a 12 hours fast, in a plain bulb from the

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subjects, with all the aseptic precautions. Blood samples were centrifuged within 30 minutes at 3000 rpm for 5 min. and serum was separated. Serum samples were stored at -20°Cuntil assayed

Serum T3, T4, TSH were estimated by ELISA method 10-12. Serum total cholesterol, HDL cholesterol by enzymatic CHOD-PAP method on Mispa semiautoanalyser13. LDL Cholesterol was calculated by using Friedewald formula14.

The data is presented as mean ±SD ,statistical analysis are carried out using unpaired students T test for all variables. P value of 0.05 or less was considered as statistically signifi cant.

RESULTS Table 1: comparison of parameters between subclinical hypothyroid cases and euthyroid

controlsParameter Controls SCH Patients P valueN 30 30T3 (ng/ml) 1.85 ± 0.96 1.52±0.38 0.091T4 (nmol/l) 89.41± 22.04 82.72 ± 17.93 0.21TSH (µIU/L) 2.58 ± 1.06 8.11± 2.54 0.001TC (mg/dl) 179.06 ± 37.10 268.10 ± 32.64 0.001LDL (mg/dl) 127.50 ± 35.63 189.89 ± 42.93 0.001HDL (mg/dl) 46.53 ± 19.89 41.17 ± 8.35 0.19LDL/HDL 3.1 ± 0.70 5.08 ± 2.74 0.004SBP (mm Hg) 122.20 ± 4.01 126.87 ± 5.72 0.007DBP (mm Hg) 81.13 ± 4.4. 88.40 ± 4.14 0.001T3=Tri-iodothyronine ; T4=Tetra iodo-thyronine;TSH=Thyroid stimulating hormone ; TC=Total

cholesterol; LDL=Low density lipoproteins; HDL=High density lipoproteinsThe table shows serum mean levels of TSH , TC , LDL ,LDL/HDL ,SBP,DBP were signifi cantly

increased in SCH patients as compared to controls where as T3 , T4,HDL did not show statistically signifi cant difference as compared to controls

Fig.1 shows the percentage change graph of the biochemical parameters in study group as compared to controls.

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DISCUSSIONSCH is more common than overt hypothyroidism and is being diagnosed more frequently in the

recent times 15. Despite this, the clinical significance of this disorder is still debatable. A controversy still exists regarding routine screening of SCH so as to prevent its progression to overt hypothyroidism16. Other debatable aspects about which definitive conclusions are yet to be drawn include the associated dyslipidemic state, cardiovascular risk, neuromuscular and psychiatric dysfunction, underlying proinflammatory state, adverse effects on fetal well being etc. 17,18.

The relationship between SCH and serum lipids remains controversial. In several cross sectional studies, SCH was found to be associated with a variable and somewhat inconsistent increase in total cholesterol, LDL-C, higher and inconsistent changes in serum HDL-C(19-21). In the Whickham survey, SCH was not related to hyperlipidemia 22. In the NHANES III, mean cholesterol levels were higher in SCH subjects as compared to euthyroids but no difference was seen in LDL-C or HDL-C. However when adjustments were made for age, sex and lipid lowering drugs, SCH was not related to increased cholesterol levels 23. In the Rotterdam study, total cholesterol was lower in SCH women than in euthyroid women 24. Bindels et al. 25 estimated that after correction for age, an increase of 1 mIU/L in serum TSH was associated with a rise in serum cholesterol of 0.09 mmol/L (3.5 mg/dL) in women and 0.16 mmol/L (6.2 mg/dL) in men. They estimated that nearly 0.5 mmol/L (20 mg/dL) of serum cholesterol could be attributed to SCH. In a study by Bauer et al., it was found that LDL-C was 13 % higher and HDL-C was 12 % higher in elderly women with elevated TSH [5.5 mIU/L] versus euthyroid women.

The LDL-C/HDL-C ratio was 29 % greater among women with elevated TSH. Women with multiple lipid abnormalities were twice as likely to have increased TSH levels. The nature and degree of dyslipidemia in overt hypothyroidism has been demonstrated in many studies and there is no doubt about the beneficial effects of thyroid substitution on serum lipids and on the risk for coronary artery disease (CAD) 26 , 27. The likelihood that a cardiovascular event will occur might not be determined solely by atherogenic lipoproteins, but rather by the balance between atherogenic and athero- protective lipoproteins [28].our study is similar to the study done by B. U. Althaus, J.-J. Staub et al 29 which showed the significant LDL/HDL ratio but their study showed significant value for HDL and LDL but our study showed significance for TC and LDL C also.

Several epidemiological and clinical studies have found that the LDL-C/HDL-C ratio is an excellent monitor for effectiveness of lipid lowering therpies. The LDL-C/HDL-C is a better predictor for risk of heart disease than LDL-C alone. The LDL-C/HDL-C reflects the two way traffic of cholesterol entering and leaving the arterial intima [30]Fernandez M, Webb D. have shown that the ratio between these particles predicts cardiovascular disease (CVD) risk better than isolated lipoprotein subfractions 31. Our study is in accordance with the study done by Fernandez M et al and Tian et al(30). Our study is also similar to the study done by Mala Mahto et al which shows that LDL/HDL ratio was more significant between the two groups. But as per their study individual parameters ie TC , HDL .LDL were not significant. But our study showed statistically significant values for TC and LDL C as well. Our study revealed a significant p value of <0.0001 when the LDL/HDL ratio was compared between the two group and also TC and LDL C were significant.

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This highlights the importance of measurement of all the lipid fractions individually and calculating the ratio of the artherogenic and artheroprotective fractions. This would reflect the actual balance between the two fractions and help in better prediction of a cardiovascular risk.

Our study showed significant difference for systolic and diastolic blood pressure between subclinical hypothyroid cases and euthyroid controls. These results are in contrast with the study done by A. Elisabeth Hak et al 32 which showed no difference for blood pressure between the two groups. But the study done by Rafael Luboshitzky et al did not show any significance for systolic blood pressure but showed a significant difference for diastolic blood pressure when compared between the two groups 33. Imaizumi et al studied only systolic blood pressure which showed no significant difference between the two groups 34. This clearly indicates that increase in blood pressure attributes to the increased risk for cardiovascular diseases in subclinical hypothyroidism.

CONCLUSIONIncreased levels of total cholesterol , LDL cholesterol and increased LDL/HDL ratio is seen

in patient with Subclinical hypothyroidism. LDL/HDL ratio is a better indicator for dyslipidemia in subclinical hypothyroid cases. This ratio can highlight a cardiovascular risk in subclinical hypothyroidism and may have the potential to become a part of the screening process to detect and treat those SCH cases with a greater cardiovascular risk. A detailed further study is required with large population size.

REFERENCES: 1. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical Thyroid

Disease Scientific Review and Guidelines for Diagnosis and Management. JAMA, January 14, 2004—Vol 291, No. 2, 228-238.

2. Fatourechi V. Subclinical Hypothyroidism: An Update for Primary Care Physicians. Mayo Clin Proc. 2009;84(1):65-71.

3. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-499

4. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007 Dec;92(12):4575-4582. Epub 2007 Oct 2.

5. Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. Thyroid. 2005;15(1):24-28.

6. Chu JW, Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab. 2001;86(10):4591-4599.

7. Rodondi N, Newman AB, Vittinghoff E, Rekeneire ND, Satterfield S, Harris TB, et al. Subclinical Hypothyroidism and the Risk of Heart Failure, Other Cardiovascular Events, and Death. Arch Intern Med. 2005;165:2460-2466.

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8. Irwin Klein and Sara Danzi. Thyroid Disease and the Heart, the American Heart Association,. Circulation. 2007;116:1725-1735.

9. Mala Mahto , Baidarbhi Chakraborthy ,Srinivas H. Gowda ,et al Are hsCRP Levels and LDL/HDL Ratio Better and Early Markers to Unmask Onset of Dyslipidemia and Inflammation in Asymptomatic Subclinical Hypothyroidism? Ind J Clin Biochem (July-Sept 2012) 27(3):284–289

10. Soos M, Siddle K. Immunol methods. 1982;51;57-68.11. Walker, W H O, Introduction: an approach to immunoassay. Clin Chem. 1977;23;38412. Schuurs AH, Van Weeman BK. Review. Enzyme-immuneassay. Clin. Chem. Acta.1977:

81;1.13. Nader R, Warnick GR. Lipids, lipoproteins, apolipoproteins and other cardiovascular risk

factors. In : Burtis CA, Ashwood ER and Bruns DA, eds. Tietz text book of clinical chemistry and molecular diagnostics, 4th edn. New Delhi : Elsevier Co., 2006; 916-52.

14. Rifai N, Iannotti E, DeAngelis K, Law T. Analytical and clinical performance of a homogeneous enzymatic LDL – cholesterol assay compared with the ultracentrifugation-dextran sulfate-Mg2+ method. Clinical Chemistry. 1998; 44(6): 1242-50.

15. Tunbridge WMG, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977;7:481–93.

16. Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345(4):260–5. 17. Ayala A, Danese MD, Ladenson PW. When to treat mild hypo- thyroidism. Endocrinol Metab

Clin N Am. 2000;29:399–415. 18. Bhaskaran S, Kumar H, Nair V, et al. Subclinical hypothyroidism: indications for thyroxine

therapy. Thyr Res Pract. 2004;1(3):10–4. 19. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P,

Koutras DA. High serum cholesterol levels in persons with’ high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998;138:141–5.

20. Iqbal A, Jorde R, Figenschau Y. Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromso Study. J Intern Med. 2006;260:53–61.

21. Asvold BO, Vatten LJ, Nilsen TI, Bjøro T. The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. Eur J Endocrinol. 2007;156 (2):181–6.

22. . Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T, Smith PA. Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. Clin Endocrinol. 1977;7: 495–508.

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23. Hueston WJ, Pearson WS. Subclinical hypothyroidism and the risk of hypercholesterolemia. Ann Fam Med. 2004;2 :351–5.

24. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witt- eman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000;132 :270–8.

25. Bindels AJ, Westendorp RG, Frolich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding?ClinEndocrinol.1999;50:217–20.

26. Duntas LH. Thyroid disease and lipids. Thyroid. 2002;12 :287–93. 27. Santi A, Duarte MM, Moresco RN, et al. Association between thyroid disease, lipids, oxidative

stress biomarkers in overt hypothyroidism. Clin Chem Lab Med. 2010;48(11):1635–9.28. Richmond W. When and how to measure lipids and their role in CHD risk prediction. Br J

Diabetes Vasc Dis. 2003;3: 191–8.29. B. U. Althaus, J.-J. staub, et al LDL/HDL-changes in subclinical hypothyroidism: possible risk

factors for coronary heart disease Clinical Endocrinology. 1988:28:157–163.30. Tian L, Fu M. The relationship between high density lipoprotein subclass profile and plasma

lipids concentrations. Lipids Health Dis. 2010;9:118. 31. Fernandez M, Webb D. The LDL to HDL cholesterol ratio as a valuable tool to evaluate

coronary heart disease risk. J Am Coll Nutr. 2008;27(1):1–5. 32. A. Elisabeth Hak et al Subclinical Hypothyroidism Is an Independent Risk Factor for

Atherosclerosis and Myocardial Infarction in Elderly Women: The Rotterdam Study Ann Intern Med. 2000;132:270-278

33. Rafael Luboshitzky et al Risk Factors for Cardiovascular Disease in Women with Subclinical Hypothyroidism THYROID 2002, Volume 12, Number 5,421-425.

34. Imaizumi et al Risk for Ischemic Heart Disease and All-Cause Mortality in Subclinical Hypothyroidism The Journal of Clinical Endocrinology & Metabolism 2004: 89(7):3365–3370

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CASE REPORT

TRANSFUSION RELATED ACUTE LUNG INJURY

L.S.Patil, S.G.Balaganur, Amith Gupta.B.ADepartment of Medicine

Shri B. M. Patil Medical College,Hospital & Research Centre, Bijapur.

ABSTRACT:Transfusion related acute lung injury is a non cardiogenic pulmonary edema or pulmonary allergic

or hypersensitivity reaction followed by blood transfusion. It occurs within 6 hours of transfusion. Key words- Transfusion, lung, injury CASE REPORT: A 60 year old male pt presented with history of breathlessness and generalized weakness since 15

days and bilateral lower limb swelling since 10 days. o/e - pt was moderately built and nourished, pulse – 90 bpm BP- 110/70 mm of Hg and pt had severe pallor and icterus , spleen palpable 3 cm from left sub costal margin . other system were clinically normal.

INVESTIGATIONS: Hb 4.4gm%.Total count of 2,000cells/cumm. DC, N-50%,L-44%,E-3%,and M-03% with ESR

of 140mm/hr . Peripheral smear: dimorphic anemia with leucopenia. Urine examination was normal Patient was transfused 1 unit of whole blood (o +). 5 hours after transfusion of blood, patient developed fever and severe breathlessness with bilateral coarse creptations repeat Chest x-ray showed pulmonary edema features. Central venous pressure was 8 cms of water. Patient was intubated and put on ventilator inspite of all these efforts patient couldn’t be reviewed and declared dead.

Fig 1 Chest X-ray before and after transfusion

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DISCUSSION: Transfusion related acute lung injury (TRALI), also known as non cardiogenic pulmonary edema

or pulmonary allergic or hypersensitivity reaction followed by blood transfusion. It is a serious pulmonary complication that as estimated incidence of 1 case in 5000 to 10000 transfusions with fatality rate of 5% to 10% .classic TRALI has an onset within 6 hours of transfusion, but an atypical form has been as occurring as late as 2 days after transfusion. Every commonly used blood component that contains plasma has been implicated in causing TRALI, including random donor platelets, which is the most common, whole blood, RBCs, apheresis platelets, fresh frozen plasma, cryoprecipitate and granulocytes. It manifests as adult respiratory distress syndrome with accelerating dyspnoea, tachypnea, hypoxemia, fever, chills, cough, and occasionally hypotension. Physical examination reveals signs of pulmonary edema with crackles and decreased breath sounds in dependent lung areas. Chest X ray show a normal cardiac silhouette with bilateral fluffy infiltrates that can progress to complete white out of the lung fields. It has been associated with allogeneic antibodies in the donor plasma component that bind to recipient leukocyte antigens, including HLA antigens and other granulocyte- and monocyte-specific antigens. In 20% of cases, no antileukocyte antibodies are identified raising the concern that bioactive lipids or other substances that accumulate while the blood product is in storage can also mediate TRALI in susceptible recipients. The diagnosis of TRALI remains principally a clinical one based on the temporal association of non cardiogenic pulmonary edema with transfusions. Treatment is focused on supportive care. Fluid support to maintain blood pressure and cardiac output and ventilatory support are the mainstays of therapy.

REFRENCES:1. Rossi’s principle of transfusion medicine.2. Popovosky MA: Transfusion related acute lung injury. Curr opin Haematology 2000;7:402-

407.3. Kopko PM Holland PV. Transfusion related acute lung injury. Br J Haematology 1999;105:322-

329.

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CASE REPORT

CHRONIC DIARRHOEA AS A PRESENTATION OF CRONKHITE - CANADA SYNDROME, A RARE NONINHERITED

GASTROINTESTINAL POLYPOSIS - A CASE REPORT

Nadagouda S.B., Biradar M.S.,Department of Medicine, Shri B.M Patil Medical College and Research Centre, BLDE University , Bijapur .

INTRODUCTION: Chronic diarrhea can be caused by various aetiologies ranging from infective, inflammatory,

malignancy, malabsorption to genetic causes. Cronkhite- Canada syndrome is one of the rare causes for chronic diarrhea.

CASE REPORT: A 48 year old male presented to medicine OPD on 21/1/2012 with history of passing loose stools

since one and a half years duration which has increased in past one month and was associated with diffuse dull aching abdominal pain. Since one month he complains of passing 3-4 episodes of loose stools after 2-3 hours of each meal which was watery in consistency and not associated with blood or mucus in it, so he had to decrease his regular food intake. Patient also started noticing splitting of nails in both upper and lower limbs since one and a half years.

On examination, patient was poorly built and moderately nourished. Alopecia, dystrophic nail changes of fingers and toes, hyperpigmentation of palms and soles were observed, oral cavity was normal except for loss of papillae and hyperpigmentation of lateral wall of buccal cavity (Fig 1,2,3) . No edema or lymphadenopthy were present. Systemic examination revealed no significant abnormality. Laboratory investigation was of normal range except for stool for occult blood was positive (table 1). Upper GI scopy showed more than 100 small polyps in stomach (fig.4), this raised our suspicion on the polyposis syndrome in patient and subjected to colonoscopy which revealed Multiple, Minute Polyps Scattered from Rectum till Caecum up to Ileocaecal valve(fig 5). Biopsy from polyps taken was suggestive of Hamartomatous Polyposis. Karyotyping was done to rule out genetic abnormality which showed normal male chromosomal pattern. His 18 year old son was evaluated clinically and found to have lentegens over the lips, so subjected to upper GI scopy to rule out familial inheritance which was normal. Hence, with detailed clinical history and clinical features and special investigations, we diagnosed the patient to have Cronkhite-Canada Syndrome. Initiated him on a high protein diet, proton pump inhibitors and empirical antibiotic therapy. Patient showed significant improvement in his abdominal complaints. Patient is being regularly followed-up for malignant transformation.

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FIGURE-1

FIGURE-2

FIGURE-3 Dystrophic nails of hands and feet.

FIGURE-4: Upper GI Scopy reveals multiple polyps in gastric antrum and duodenum.

FIGURE-5: Colonoscopy reveals multiple polyps in colon.

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Table 1. Laboratory ExaminationsHaemoglobin 14.8 gm%Total WBC Count 12900 cells/cummEosinophils 5%ESR 5mmTotal Protein 5.8 g/dl Albumin 3.0 g/dl

Stool Examination - Occult blood presentTable – 2

USG – Thyroid Well defined heterogeneous nodule in left lower part of left lobe measuring 7x5 mm – suggestive of Adenoumatous Nodule.

Upper GI Scopy More than 100 small polyps seen in stomach.Colonoscopy Multiple, Minute Polyps Scattered from Rectum till Caecum up to

Ileocaecal valve.Histopathological Examination

Suggestive of Hamartomatous Polyposis.

Karyotyping Normal Male Chromosomal pattern.DISCUSSION:Diarrhea is passage of abnormally liquid or unformed stool at an increased frequency, said to

be chronic if persistent for more than 4 weeks in duration. Chronic diarrhea warrants evaluation to exclude underlying pathology, as most causes are non-infectious. In estimated two-third of the cases remains unclear after initial encounter and further testing is required. Stool collection and analysis can yield important objective data, Upper Endoscopy and Colonoscopy with biopsies to rule out structural or occult inflammatory diseases.

Cronkhite-Canada Syndrome (CCS) is a rare non-familial polyposis syndrome presenting as chronic diarrhea. CCS is characterised by epidermal manifestations like alopecia, dystrophic nail changes and hyperpigmentation . GI changes include generalized hamartomatous polyposis .

The mucosal proliferation leads to fluid and electrolyte abnormalities, malnutrition, malabsorption and GI bleeding. These changes lead to clinical symptoms like diarrhea, abdominal pain and malnutrition. Diarrhea is multifactorial,the beneficial effects of antibiotics are attributed to small bowel overgrowth. Steroids are most likely effective as anti-inflammatory agents. Polyps are believed to contribute to diarrhea. Data from most cases support the belief that ectodermal features are the result of malnutrition but many symptoms and signs appear or remit in a manner inconsistent with this theory. The aetiological factors leading to progression, spontaneous remission, or optimal treatment has not been established. Current understanding of the disease is based on small series of cases reported since it was first described by Cronkhite and Canada in 1955.

The prevalence of GI malignancy is about 10%. Most of the complications encountered are

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manifestations of polyposis. Some patients with CCS have been diagnosed after presenting initially with eosinophilic gasteroenteritis and intestinal candidiasis.

CONCLUSION: Chronic diarrhea associated with malena has to be evaluated thoroughly with upper GI scopy

and Colonoscopy to rule out or confirm rare causes, such as Cronkhite-Canada syndrome for better management.

REFERENCES:1. Michael Camilleri, Joseph A. Murray “Diarrhoea and Constipation” Harrison’s principle of

internal medicine 18th edition.volume 1, pp 308-319.2. SP Lipin, Baby Paul, E Nazimudeen et al “Case of Cronkhite-Canada Syndrome shows

improvement with enternal supplements” JAPI. 2012;61-63.3. S.H Itzkowitz, Jonathan Polak “Colonic Polyp and Polyosis Syndrome” Sleisenger and

Fordtran’s Gastrointestinal and Liver Disease 9th Edition Vol 1,PP: 2155-21904. R.Chandrashekar, D.K.Brown, A>N>Waliker et al “Cronkhite-Canada Syndrome sustained

remission after corticosteroid treatment” American Journal of Gastroenterology. 2003;98:1444-1446.

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CASE REPORT

TUBO OVARIAN COMPLICATIONS FOLLOWING HYSTERECTOMY- A CASE REPORT

Jaju Purushottam B, Ashwini V, S.R.Bidri, Jayashree Sajjanar, Sangamesh M. Department of Obstetrics and Gynecology, Shri B.M.Patil Medical College Hospital and research centre,

BLDE University, Bijapur-586103,Karnataka.India

ABSTRACT Generally hysterectomy is regarded by females as end of gynaecological problems but emergence

of a pelvic mass subsequently has profound physical and psychological impact . Apart from genital tract malignancies various benign diseases may necessitate hysterectomy such as DUB, fibroids , endometriosis, adenomyosis, prolapse, ovarian tumours and massive obstetric haemorrhage. Pelvic masses after hysterectomy can arise from conserved ovaries, ovarian remnants, fallopian tube, broad ligament, retroperitoneal spaces, bladder and bowel, Ultrasound being a diagnostic tool. Here, we are reporting a case of pelvic mass following hysterectomy done for chronic cervicitis and diagnosed as hydrosalpinx and ovarian cyst on ultrasound. Patient underwent bilateral salphingoophorectomy and diagnosis was confirmed by histopathology report.

Keywords : hydrosalpinx, chronic cervicitis, ovarian cyst, ultrasound, hysterectomy.INTRODUCTIONDespite new developments in the treatment of gynaecological problems, Hysterectomy remains

a common surgical procedure .Hysterectomy rates vary greatly internationally from 55 per 10,000 women in North America and 28 per 10,000 women in Britain, 10 per 10,000 women in Denmark 1 , 4-6 per 100 women in India.Hysterectomy rates vary in countries according to both patient related factors such as race, socio economic status, educational status, private health insurance and attitude towards surgery and gynaecological problems .

At the time of hysterectomy the ovaries and tubes can either be removed or retained. Oophorectomy does not add significantly to the duration or immediate complication of hysterectomy but may have implication for short and long term health.Salphingoophorectomy is more commonly performed at the time of abdominal as compared to vaginal hysterectomy probably referring indication for the procedure as well as ease of surgical access. 2 General practice is to conserve the tubes also along with ovaries whenever ovarian conservation is required. There is certainly beneficial effects from ovary but infection may continue to be present in the tube and may manifest as hydrosaplinx and chronic pelvic pain .

The American College of Obstetricians and Gynaecologists (ACOG) has recently changed its recommendation regarding retention or removal of normal ovaries at the time of hysterectomy. They suggest that women aged 45 years should be the cut off for oophorectomy. Strong consideration should be made for retaining normal ovaries in pre menopausal woman who are not at increased genetic risk of ovarian cancer. (http://www.acog.org/). A recent systematic review concluded that

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there is currently no good studies of the benefits or harms of removing normal ovaries at the time of hysterectomy3.

CASE REPORTWe are reporting a case of Mrs. X, Para 3, Living 3, aged 50 years, with complaints of lower abdominal

pain for 2 months. Patient had undergone hysterectomy 10 years back for chronic cervicitis. On per abdominal examination there was tenderness present in right iliac fossa. Per Speculum examination showed vault healthy and minimal white discharge was present .On per vaginal examination there was tender mass of about 2×3 inches at the right side of vaginal vault. Ultrasound showed well defined tubular cystic lesion in the right adnexal area with features of hydrosalpinx measuring 7 X 3.7 cm and multiple right ovarian cyst with evidence of internal echoes in one of the loculation. At laparotomy there was right sided hydrosalpinx of about 8×4.5 cm, small cystic ovary 4X3 cm on the right ovary. On the left side, tubo ovarian adhesions were present , fallopian tube was thickened and ovary was unhealthy and enlarged. There were also adhesions present between omentum and cystic mass. And hence, bilateral salphingoophorectomy was done.

HPR report confirmed hydrosalpinx of right tube and simple ovarian cyst of right side and chronic salphingio ophiritis of left side. Post operative period was uneventful.

DISCUSSIONPelvic mass may be the result of pelvic inflammatory disease4 usually as a consequence of an

ascending infection by Chlamydia or Gonorrhoea and sometimes tuberculosis . Other causes of adhesion are previous surgery and endometriosis. Symptoms can vary. The hydrosalpinx in this case was due to fimbrial block caused by infection and adhesions following hysterectomy. Common practice is to preserve healthy ovaries during hysterectomy if the age of the woman is less than 45 years.

Common indications for prophylactic oopherectomy at the time of hysterectomy are :1) Reduction in the future risk of ovarian cancer : particularly in the post menopausal women.

Hysterectomy alone can reduce the risk of ovarian cancer by around 36% compared with an intact uterus and ovaries and this protective effect continues for upto 15 years5 .Sometimes the decision may be left until the time of surgery with the plan to retain the ovaries if they appear normal . It is not known whether a surgeon’s impression of “ normality “ equates reliably to histologically confirmed ovarian pathology . Clinical experience suggests that there is likely to be a high chance of false positives.

2) Hormonal effects : Postmenopausal ovaries continue to be active and produce estradiol (at low levels) and testosterone 6. Total testosterone concentrations are maintained across the menopausal transition, with a fall in sex hormone-binding globulin and hence a rise in free testosterone 7. Ovarian testosterone undergoes peripheral conversion to estrone, and may act independently on libido, bone health and well-being.

3) Vasomotor symptoms: Menopausal symptoms following surgical menopause may be more severe and long lasting than those seen following spontaneous ovarian failure 8. Recent cross-sectional

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data indicate that HT following bilateral salpingoophorectomy (BSO) as a risk-reducing procedure may not be effective in managing menopausal symptoms.

4) Cardiovascular health: Cardiovascular disease (CVD) and particularly coronary heart disease (CHD) is a leading cause of death in older women, and the rate increases following menopause 9. The reasons for this are not fully known, but may relate to an accelerated rise in cholesterol levels, blood pressure and insulin, which primarily relate to increased body weight following the menopause transition .In the Women’s Health Initiative (WHI) study, oopherectomy and hysterectomy were associated with a 2-fold increased risk of coronary artery calcification compared with those whose ovaries were retained 10. This was partially ameliorated when estrogen was used. A recent meta-analysis demonstrated that natural menopause did not increase the risk of CVD (RR: 1.14, 95% CI: 0.86–1.51) but oophorectomy, even at a mean age of 50 years appeared to increase the risk (RR: 2.62, 95% CI: 2.05–3.35) and oophorectomy at younger than 50 years had a substantial negative impact on CVD (RR: 4.45, 95% CI: 2.56–8.10) 11.

5) Cognitive function and mental health: A systematic review concluded that whilst smaller prospective studies have found that surgical menopause is associated with specific deficits in the memory (visual and verbal) and verbal fluency domains, limited data from randomized controlled trials have generally found no effect of surgical menopause on cognitive functioning 12.

6) Osteoporosis and fracture risk: Premature menopause is a well-established risk factor for osteoporosis. The risks of osteoporosis and fracture can be reduced by taking hormonal therapy in women with premature or early menopause.

7) Quality of life and sexual function: Overall, data from high-quality studies show that quality of life, psychological well-being and sexual function improve after hysterectomy for benign disease 13. However, there are limited data indicating how oophorectomy impacts on these quality of life outcomes. Most studies suggest that increasing age and postmenopausal status impact negatively on sexual function

ACOG guidelines states that women with endometriosis, pelvic inflammatory disease and chronic pelvic pain are at higher risk of reoperation; therefore, the risk of subsequent ovarian surgery, if the ovaries are retained should be weighed against the benefit of ovarian retention in these patients.

Even if the ovaries are preserved, the tubes should be removed because they carry the risk of infection and later developing peritubal adhesions , tubo ovarian mass, salphingitis and tubo ovarian abscess . Risks with ovarian conservation are ovarian malignancy , residual ovarian syndrome, ovarian cysts, oophoritis , ovarian abscess and ovarian adhesions .

CONCLUSIONThe decision to remove healthy ovaries in a woman of any age at a time of hysterectomy for benign

disease should only be made following adequate and individualised counselling of the patient and and the benefits of conservation or removal. Irrespective of ovarian conservation both the tubes should be removed during hysterectomy to prevent further complications of salphingitis like hydrosalpinx, peri tubal adhesions , tubo ovarian mass and tubo ovarian abscess.

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Ovarian cyst hydrosalphinx

REFERENCES 1. M. Hickey, M.Ambekar,I.Hammond. Should The Ovaries Be Removed or Retained At The Time

of Hysterectomy For Benign Disease. Human Reproduction Update ,2010; Vol.16,No.2.131-141,

2. Davies A, O’Connor H, Magos AL. A prospective study to evaluate oophorectomy at the time of vaginal hysterectomy. Br J Obstet Gynaecol 1996;103:915–920.

3. Orozco LJ, Salazar A, Clarke J, Tristan M. Hysterectomy versus hysterectomy plus oophorectomy for premenopausal women. Cochrane Database Syst Rev 2008;16:CD005638.

4. Morse AN, Schroeder CB,Margina JF et al .The risk of hydrosalpinx formation and adnexectomy following tubal ligation and subsequent hysterectomy . Am J Obstet Gynecol. 2006 .May; 194(5): 1273-6

5. Chiaffarino F, Parazzini F, Decarli A, Franceschi S, Talamini R, Montella M, La Vecchia C. Hysterectomy with or without unilateral oophorectomy and risk of ovarian cancer. Gynecol Oncol 2005;97:318–322.

6. Rinaudo P, Strauss JF III. Endocrine function of the postmenopausal ovary. Endocrinol Metab Clin North Am 2004; 33:661–674.

7. Burger H. The menopausal transition–endocrinology. J Sex Med 2008; 5:2266–2273.Bachmann GA. Vasomotor fl ushes in menopausal women. Am J Obstet Gynecol 1999;180:S312–

S316. 8. Lobo RA. Surgical menopause and cardiovascular risks. Menopause 2007;14:562 566 Allison

MA, Manson JE, Langer RD, Carr JJ, Rossouw JE, Pettinger MB, Phillips L, Cochrane BB, Eaton CB, Greenland P et al. Oophorectomy, hormone therapy, and subclinical coronary artery disease in women with hysterectomy: the Women’s Health Initiative coronary artery calcium study. Menopause 2008; 15:639–647.

9. Atsma F, Bartelink ML, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006;13:265–279

10. Vearncombe KJ, Pachana NA. Is cognitive functioning detrimentally affected after early, induced menopause? Menopause 2009; 16:188–198.

11. Rhodes JC, Kjerulff KH, Langenberg PW, Guzinski GM. Hysterectomy and sexual functioning. JAMA 1999; 282:1934–1941.

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CASE REPORTPOSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME: A

CASE REPORTSharan Badiger1, Mudanur S.R.2, Deepak Kadeli1, Bhairavi Joshi2.

1Department of Medicine, Shri B.M.Patil Medical College Hospital and research centre, BLDE University, Bijapur-586103,Karnataka.India

2Department of Obstetrics and Gynecology, Shri B.M.Patil Medical College Hospital and research centre, BLDE University, Bijapur-586103,Karnataka.India

ABSTRACTPosterior Reversible Encephalopathy Syndrome is a rare condition which presents with seizures,

headache and cortical blindness. It is associated with white matter changes on imaging secondary to vasogenic edema.It is associated with hypertension during peripartum period but can be seen in others conditions as well. We report here a twenty one year old primigravida who presented with imminent signs of eclampsia and cortical blindness. The patient was diagnosed with posterior reversible encephalopathy syndrome after thorough work up. Patient was treated with antihypertensive and showed complete improvement. Posterior Reversible Encephalopathy Syndrome is a rare but important condition which requires early recognition and treatment to prevent morbidity and mortality in pregnancy and postpartum.

Keywords : Hypertension, Peripartum, White matter changesINTRODUCTION The term Posterior Reversible Encephalopathy Syndrome (PRES) was first coined by Dr Judy

Hinchey when she discovered this reversible phenomenon by assessing the Computed Tomography (CT) and Magnetic Resonance Imaging(MRI) recordings showing white matter abnormalities without infarction in patients who mainly presented with headache, decreased alertness, altered mental functioning, seizures, and visual loss, including cortical blindness1. Since the definition of the syndrome more and more cases are being categorized as PRES.

The causes are varied ranging from hypertensive encephalopathy, postpartum eclampsia, delayed postpartum preeclampsia and other hypertensive states which account for more than half of the cases 2. Other causes include renal diseases, secondary to immunosuppressive drugs for malignancy and transplantation. Though more cases of PRES are being reported it’s still considered a rare diagnosis. It is important to recognize it early and differentiate it from venous thrombosis or stroke which have completely different line of treatment and are usually suspected in such presentations. The delay in diagnosis and wrong management can cause additional complications and permanent neurological damage.

CASE REPORT A 21 year old female presented to the labor room of our hospital with three episodes of convulsions

in the past three hours, she was a primigravida with eight months of amenorrhea. The patient had been having headache, blurring of vision, vomiting since the past one day which were sudden in

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onset. There was progressive deterioration of symptoms in the next 24hrs .The patient had a normal antenatal period until the onset of these symptoms. The first antenatal check up done in second trimester had normal recordings of blood pressure and USG scan showing single live fetus with no abnormalities. The patient had no previous history of hypertension. General physical examination was normal. Central nervous system examination revealed diminution of vision in both eyes with regard to perception of hand movement. Pupillary reactions were normal, a fundoscopic examination of eye was normal. Patient had normal power tone and reflexes. Cardiovascular, respiratory and per abdomen system examinations were normal. The patient was treated with a loading dose of Magnesium sulphate with maintenance intramuscular injections for imminent signs of eclampsia which was stopped after two doses. Non Stress Test showed fetal distress, magnesium sulphate was discontinued and the patient was posted for emergency Lower Segment Caesarian Section . The procedure was uneventful with extraction of a live male baby. The patients complete blood picture, liver function tests, kidney function tests, clotting parameters, and electrocardiogram were within normal limits. Urine examination was normal. The patient was diagnosed with cortical blindness and a CT with MRI advised. CT and MRI of the brain showed symmetrical hyper intense signals in the white matter of the bilateral occipital lobes in T2-weighted and FLAIR sequences. (Fig 1)

Fig 1. Magnetic Resonance Imaging (MRI) showing hyperintensities in bilateral occipital lobesThe patient was diagnosed with Posterior Reversible Encephalopathy Syndrome. Regular blood

pressure (BP) recordings were done. The mean BP was around 150/90 mm of Hg.On fourth postnatal day the BP was 160/90 mm of Hg and the patient was treated with Nifedipine 10 milligrams, per orally twice a day. BP decreased the next day but the antihypertensive was continued until her discharge. Patient had complete resolution of symptoms and was discharged on the 10th postnatal day.

The patient returned for follow up after 1 month and had no residual symptoms. Repeat MRI was done which showed complete disappearance of hyper intensities.(Fig 2).

Fig 2. Repeat MRI of same patient after one month showing clearing of hyperintensities in the occipital lobes.

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DISCUSSIONAdvances made in imaging and increasing availability of CT and MRI in tertiary hospitals has

made it possible to detect more cases of PRES. Cerebral edema, secondary to failure of cerebral auto regulation causing hyper perfusion has been widely cited as the possible pathophysiology of PRES. Another theory suggests ischemic damage secondary to vasoconstriction induced hypo perfusion which again causes cerebral edema3. Vasogenic cerebral edema is easily picked up by CT and MRI which are very sensitive to changes in the distribution of water in the brain and make it possible to detect white-matter edema even in its early phases. Traditionally CT changes have been mainly reported to be seen in the posterior parietal–temporal–occipital regions of the brain1 but some studies show frontal lobe preponderance2. Atypical features include, cortical, brainstem lesions, hemorrhage into lesions, and unilaterality4.

The patient in this case had presented with signs of imminent eclampsia. The initial differential diagnoses were cerebral venous sinus thrombosis, pregnancy-related stroke. After the CT and MRI showed occipital white matter hyper densities and the patient’s symptoms started resolving PRES was considered as another differential. The patient followed up after one month with complete recovery. The repeat MRI showed complete resolution of the hyperintensities.The diagnosis of PRES was confirmed.

Since the symptoms of PRES which include seizures, headache and visual disturbances are seen in preeclampsia and eclampsia it is easy to miss the diagnosis of PRES. In this case when the diminution of vision turned to near complete loss of vision, which did not improve even after delivery, further work up was done. This case emphasizes the need for early work up including imaging for cases who present with hypertension with persisting loss of vision.

ACKNOWLEDGEMENTSWe would like to thank the Departments of Ophthalmology and Radiodiagnosis for their

contributions.REFERENCES

1. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494-500.

2. Matthys LA, Coppage KH, Lambers DS, Barton JR, Sibai BM. Delayed postpartum preeclampsia: An experience of 151 cases. Am J Obstet Gynecol 2004;190:1464-1466.

3. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: Controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008;29:1043-1049.

4. Kauntia R, Valsalan R, Seshadri S, Pandit VR, Prabhu MM. Late postpartum preeclampsia with posterior reversible encephalopathy syndrome. Indian J Med Sci 2009;63:508-511.

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CASE REPORTDEATH SEAT - A CASE REPORT

Gannur Dayanand G, Nuchhi U C, Yoganarasimha kDepartment of Forensic Medicine, Shri B.M.Patil Medical College Hospital and research centre,

BLDE University, Bijapur-586103,Karnataka.India

ABSTRACTMan invented wheels accidentally and ever since he has making accidents! Accidents just do not

happen. They are caused. The reason may be the man, the machine or the material. Most of the time it is the human behavior that results in the avoidable misfortune.

Key words: Pillion Rider, Road accidents, Death seat.INTRODUCTIONIndia has experienced rapid growth in motorization in the last decade, with concomitant increases

in road traffic injury (RTI) related mortality being observed1,2 . Pedestrians, motorised two-wheeled vehicle (MTV) users, and cyclists are the most vulnerable road user groups in terms of injuries and fatalities resulting from road traffic crashes in India1,3,6. In actual numbers, over 105,700 people died and 452,900 were injured due to RTI in India in 2006 alone, with MTV users accounting for 17.8% of the fatalities7. Moreover, fatalities due to RTI in India are projected to increase by 150% by the year 20205 with the majority of this increase being among users of MTV5,6 With MTV representing 70% of all vehicles registered in India in the year 2004 8, the centrality of MTVs as a means of daily transport in India is clear.

CASE REPORTThe victim, 22 years old was a pillion rider. The motor cyclist was overtaking another vehicle.

Suddenly pillion rider lost his balance stretching his legs wide. One leg got caught in the wheel of the truck coming from the opposite direction and dragged him to his death. The person who was driving the motor cycle sustained minor injuries.

Autopsy Findings: External Findings: Dead body of an adult male aged about 34 years, measuring 5 feet and 10 inches in length, well built and moderately nourished; dark brown in complexion. Eyes closed, pupils dilated and fixed post mortem staining present over the back, rigor mortis well appreciated all over the body.

External Injuries: Grazed abrasion seen over outer aspect of left forearm 4 cm away from elbow joint measuring 6x2

cms. A pressure abrasion seen over the right elbow joint. A pressure abrasion seen over the left iliac fossa measuring 11x6 cms. Grazed abrasion, 8x4cms over right side of right knee joint.

A Grazed abrasion seen on inner aspect of the left lower limb measuring 26x5 cms on the upper

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part the medial side of left leg. Grazed abrasion seen on the back of the upper left calf over an area & measuring 14x7cms. A lacerated wound seen on upper part of the inner aspect of the right thigh exposing the muscles, vessels & tendons with fracture of right hip bone, measuring 21x8x10cms & extending to perineal area. Avulsion of the skin of the scrotum exposing the left testis. Left leg is in abnormal anatomical position, externally rotated with abnormal movement of hip joint (fracture of upper end of femur). On dissection there is resection of lumbo- sacral region.

Internal Examination: All the vital organs(brain, heart & lungs) were pallor and intact.Stomach- contains 50 ml of dark colored fluid, no unusual smell, mucosa normal. Other organs were intact and congested. Cause of Death: “Death is due to complication (haemorrhage &shock) secondary to the injury

sustained which are consistent with the alleged history of Road Traffic Accident.”

Figure-1 ,Left leg is in abnormal anatomical position, externally rotated with abnormal movement of hip joint (fracture neck of femur) & abducted.

Figure-2A lacerated wound seen on upper part of the inner aspect of the right thigh exposing the muscles, vessels & tendons with fracture of right hip bone. Avulsion of the skin of the scrotum exposing the left testis.

Figure-3, Resection of lumbo- sacral region.

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PreventionWear Full Protective Motorbiking Gear- Gloves, jacket, Motorbike trousers, Don’t Shift Your

Weight On the Bike.Hold Onto the Driver’s Waist, Not Shoulders. Using Hand Signals to Communicate on a Motorbike.Keep Your Feet Up When the Bike is Stationary.Dress Warmly on a Motorbike.Drive Only with a Biker You Trust. Weight and Age of the pillion rider is crucial.Make sure the passenger wears a helmet and a jacket.Give a few instructions to the pillion rider. Talk less while riding.

DISCUSSIONPillion riding is quite a challenging task and calls for a lot of responsibility, as the rider not only

needs to take care of his/her safety but also ensure the safety of the pillion rider. Simply following traffic Rules, commonsense & responsible behavior prevents an imminent out come.

REFERENCES1. Gururaj G. Road traffic deaths, injuries and disabilities in India: current scenario. Natl Med J

India. 2008;21:14–20. 2. Peden M, Scurfield R, Sleet D, Mohan D, Hyder AA, Jarawan E, Mathers C. World report on

road traffic injury prevention. Geneva: World Health Organisation; 2004. 3. Dandona R, Kumar GA, Raj TS, Dandona L. Patterns of road traffic injuries in a vulnerable

population in Hyderabad, India. Inj Prev. 2006;12:183–188. doi: 10.1136/ip.2005.010728. 4. Dandona R, Mishra A. Deaths due to road traffic crashes in Hyderabad city in India: need for

strengthening surveillance. Natl Med J India. 2004;17:74–79. 5. Kopits E, Cropper M. World Bank Policy Research Working Paper No 3035. Washington DC:

The World Bank; 2003. Traffic Fatalities and Economic Growth.6. Mohan D, Tiwari G. Reflections on the transfer of traffic safety knowledge to motorising

nations. Melbourne: Global Traffic Safety Trust;. Road safety in low-income countries: issues and concerns regarding technology transfer from high-income countries. 1998; 27–56.

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MEDIAL EDUCATION

GUIDELINES FOR CONSTRUCTING MULTIPLE CHOICE QUESTIONS (MCQ)

Surekha B. HippargiProfessor of Pathology, Member, Department of Medical Education,

Shri B. M. Patil Medical College, Hospital & Research Centre, Bijapur.

ABSTRACT: Multiple choice questions (MCQs) provide faster ways of assessing student learning and is

important method of objective assessment. MCQ is used in most of the entrance examination. It is difficult and time-consuming to construct MCQ especially in cases where higher order cognitive skills are being assessed. If guidelines are correctly followed by faculty, it is not difficult to prepare a good quality MCQs., which fall under principles of student assessment.

INTRODUCTION:Assessment is one of the important components of teaching and learning cycle, it is the major

drive of students’ learning, and it is said that the ‘assessment tail wags the curriculum dog’. Objective assessment is becoming more important in the field of education both for summative & formative purposes. One of the most commonly adopted methods of objective assessment is Multiple Choice Questions (MCQ), in which respondents are asked to select the best possible answer (or answers) out of the choices from a list.

MCQ type is used in most entrance examination due to the logistical advantage because they can provide a large number of examination items that encompass many content areas, can be administered in a relatively short period. Genuine issues related to MCQ are that, they are difficult and time-consuming to construct especially in cases where higher order cognitive skills are being assessed. Cueing effect can result in guessing & can lead to failure in accurate interpretation of scores & impact an assessment, hence items must be constructed free of such flaws & should be able to discriminate between good & average/poor performer. This can be achieved by increasing validity & reliability of the testing by prevalidation & post validation of an MCQ Item

COMPONENTS OF MCQ:Item - The entire unit of MCQ which consists of a stem and options.Stem - Question, statement or lead-in to the question.Alternatives/Options/Choices - The choices that follow the stemKeyed Response - The correct option/optionsFoils/distracters –Incorrect choices /options

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FORMATS OF MULTIPLE-CHOICE QUESTIONS:SINGLE CORRECT ANSWER/ONE BEST RESPONSE TYPE/TYPE A:Most common formatUsually tests only recall of factsCan be constructed for problem solving abilities, interpretation or analysisFour to five alternativesDifficulty – to find plausible alternativesItems of the negative type of single best response - Student is directed to identify either the

alternative that is an incorrect answer, or the alternative that is the worst answer.MULTIPLE COMPLETION TYPE (TYPE K) RESPONSE:Two or more of the alternatives are keyed as correct answers & remaining alternatives serve as

distracters. Answers with the help of slandered code – A if 1,2 & 3; B if 1& 3; C if 2 & 4; D if only 4 & E if all are correct. The student is directed to identify each correct answer.

Can be scored in different ways. Scoring done on ‘all-or-none basis’ or scoring each alternative independently.

MULTIPLE TRUE / FALSE COMPLETION TYPE: Most common format in PLAB exams.RELATIONSHIP ANALYSIS TYPE (TYPE E):Very useful to test higher level of cognitionTwo statements are asked to respond by choosing –A, If both statements are true & casually relatedB, If both statements are true & not casually relatedC, If the first statement is true & second falseD, If the first statements are false & second trueE, If both statements are falseMATCHING THE FOLLOWING TYPE:Less commonly usedNumber of choices on right side should be more than left side.PROCEDURAL GUIDELINES:Clear instruction for the process of marking the right choice/choices on the answer sheet.Include MCQ of varying levels of difficulty.

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Format the questions vertically, not horizontally (i.e., list the choices vertically)Time 40-60 seconds/MCQCONTENT-RELATED GUIDELINES:Question should be based on student learning objective of the course. Focus on a single problem or idea for each question.Keep the vocabulary consistent with the students’ level of understanding.Avoid providing cues from one question to another; keep each question independent of one

another. Use examples from course materials as a basis for developing your questions.Avoid overly specific knowledge when developing questions.Avoid verbatim phrasing when developing the questions.Use multiple-choice to measure higher level learning/knowledge.STEM CONSTRUCTION GUIDELINES:Include the central idea.State the stem in either question form or completion form.The blank in completion questions should always be at the end of the stem.Stem directions should clearly indicate to students exactly what is being asked. Word the stem positively; avoid negative phrasing such as “not” or “except.” If this cannot be

avoided, the negative words should always be highlighted by underlining or capitalization: Which of the following is NOT an example ……

Avoid giving clues such as linking the stem to the answer (…. Is an example of an: test-wise students will know the correct answer should start with a vowel)

GUIDELINES FOR DEVELOPING THE OPTIONS:Place options in logical or numerical order.Use letters in front of options rather than numbers. Keep options independent.Keep all options homogeneous in content.Keep the length of options fairly consistent. Avoid or use sparingly, the phrase all of the above & none of the above.Provide three to five options for each question. Optimum: FOURPhrase options positively, not negatively.Avoid giving clues through the use of faulty grammatical construction.

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None of the above should be used carefully Avoid all of the aboveAvoid specific determinates, such as never, always completely and absolutely etc.Position the correct option so that it appears about the same number of times in each possible

position for a set of questions.Make sure that there is one and only one correct option in case of single response MCQ.The greater the similarity among alternatives, the greater the difficulty.GUIDELINES FOR DEVELOPING DISTRACTERS:Use plausible distracters.Incorporate common errors of students in distracters.Use familiar yet incorrect phrases as distracters.Use true statements that do not correctly answer the questionAvoid distracters that can clue test-wise examinees.Avoid technically phrased distracters.Distracters that are not chosen by any examinees should be replaced. DISTRIBUTION OF MCQS: Topics No. of Items Must know 70 Desirable to know 20 Nice to know 10 ------- Total 100 VALIDATION – TWO STAGES:PRE-VALIDATION Analysis of item done prior to examination (with 4-6 subject experts, colleagues)To avoid inclusion of defective itemsSteps in prevalidation are – relevance to learning outcome, clarity, appropriateness, level of

cognition, grammar of construction Distracters and their plausibilityPOST –VALIDATION(ITEM ANALYSIS) Analysis of item done after the examinationItem analysis is an excellent way to periodically check the effectiveness of your test items. It

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identifies items that are not functioning well, thus enabling you to revise the items, remove them from your test, or revise your instruction, whichever is appropriate.

The following Check-list would help to ascertain the validity of MCQs and ensures reliable (objective) assessment of candidates.

CHECKLIST FOR:Item as a wholeIs the direction clear Is each item wholly independent of others? Are all unrelated details eliminated? Does the item test an important learning outcome/important content area? Is it specific? Is it brief and not too involved?Is the level of difficulty / discrimination appropriate? Is the appropriate time for the item is indicated?Are there clues which suggest the correct answer? Are negative statements used with care and appropriately emphasized? Is the type of item the best one for the particular point or problemStem: 1. Is it clear, concise and unambiguous? 2. Does it ask for an opinion? 3. Is it devoid of expressions like fairly high, considerably greater, etc? 4. Are words like never, always, usually, sometime, etc., used with caution? 5. Are double negatives avoided? C. Options: 1. Are they logical and plausible? 2. Are they parallel and homogenous? 3. Do all options complete the stem grammatically? 4. Are all distractors functional? 5. Is care exercised in using none of the above as distractor? D. Key (correct answer): 1. Is it undeniably the only correct response?

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2. Are alphabets corresponding to the key equally distributed? 3. Is key to an item provided by data in another item? 4. Is care taken not to use words in key which are synonyms or very similar to words

in the stem? REFERENCES:

1. Beth Bierer, , Christine A. Taylor, Elaine F. Dannefer. Evaluation of Essay Questions Used to Assess Medical Students Application and Integration of Basic and Clinical Science Knowledge. Teaching and Learning in Medicine 2009; Oct 21(4): pages 344 —350.

2. Burton SJ, Sudweeks RR, Merrill PF, Wood B. Hot to Prepare better Multiple Choice Items: Guidelines for University FacultyBrigham Young University Testing Services and The Department of Instructional Science 1991.

3. Chris Candler. Effective Use of Educational Technology in Medical Education - Colloquium on Educational Technology: Recommendations and Guidelines for Medical Educators, AAMC Institute for Improving Medical Education. March 2007.

4. Ciraj AM. Multiple Choice Question. In Singh T & Anshu. Principles of Assessment in Medical Education 1st Edition Jaypee Brothers Medical Publications.2012:88-106

5. N Ananthakrishnan. Item Analysis: Validation & Banking of MCQ. I N Ananthakrishnan, K R Sethuraman, Santoshkumar. Medical Education – Principles & Practice 2nd Edition. Pondicherry, India: NTTC;2000:131-138.

6. N Ananthakrishnan. Multiple Choice Questions – facts & fantacies. I N Ananthakrishnan, K R Sethuraman, Santoshkumar. Medical Education – Principles & Practice 2nd Edition. Pondicherry, India: NTTC;2000:119-130.

7. N Ananthakrishnan. Principles of Evaluation. In N Ananthakrishnan, K R Sethuraman, Santoshkumar. Medical Education – Principles & Practice 2nd Edition. Pondicherry, India: NTTC;2000:99-106.

8. TOOLBOX OF ASSESSMENT METHODS: A Product of the Joint Initiative ACGME

Outcomes Project Accreditation Council for Graduate Medical Education American Board of Medical Specialties (ABMS) Version 1.1 September 2000.

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