immediate effect of a slow pace breathing exercise bhramari

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The composition and quantitative analysis of urinary calculi inpatients with renal calculi

S Jawalekar,1 VT Surve2 and AK Bhutey3

1Department of Biochemistry, M. G. M. Medical College, Kamothe, Navi Mumbai, 2Dr. Ulhas Patil Medical College, Jalgaon, and3Grant Medical College, Mumbai, India

Corresponding author: Dr. Seema Jawalekar, Associate Professor, Department of Biochemistry, M. G. M.. Medical College, Kamothe,Navi Mumbai, India; e-mail: [email protected]

ABSTRACT

To get complete information about the chemical composition and physicochemical principles underlying theformation of stone there is a need for more precise information. At present there is no single analytical procedurethat provides an exact quantitative analysis of urinary calculi. In this present procedure it is assumed that onlycalcium oxalate monohydrate, hydroxyapatite, or magnesium ammonium phosphate hexahydrate are presentin stone, therefore the percent chemical composition of stone is calculated on the basis of molecular weight ofan element and related molecular formula of the stone. By analysis of 100 stones the chemical compositionobserved with Mean ± SD value for calcium is 25.68 ± 5.38, for Calcium oxalate hydrate crystal is 32.84 ±17.28 which contains oxalic acid 20.35 ± 10.70, for Apatite crystal is found to be 41.70 ± 16.56 which containsinorganic phosphate 8.09 ± 3.08. Total uric acid found in these stones is 27.12 ± 11.42. Major component arecalcium oxalate 32.8% (combined monohydrate and dihydrate), Phosphate 41.7%, Magnesium ammoniumphosphate hexahydrate 3.3% and uric acid 27.1%. No pure stone was obtained. Calcium oxalate was present innearly all stones, and the majority of renal calcium stones contains mixtures of calcium oxalate and calciumphosphates in addition some contains uric acid or magnesium ammonium phosphate. The mixture of calciumoxalate / uric acid / magnesium ammonium phosphate hexa hydrate has never been observed.Keywords: Calcium oxalate, hydroxyapatite, uric acid, urinary calculi.

INTRODUCTION

Better understanding of the physico-chemical principlesunderlying the formation of stone there is a need formore precise information, particularly with regard to thecommon calcium containing stones. Qualitativechemical tests provide only a rough indication of therelative amounts of the different constituents in a mixedstone and the results may be misleading. A number ofphysical methods have been used for the analysis ofcalculi including optical crystallography, x raydiffraction, infrared spectroscopy, x ray spectroscopyand thermogravimetry, but these techniques requireelaborate apparatus, are generally only semi quantitativeand do not detect minor constituents of mixed calculi.1

Chemical analysis therefore remains the most convenientprocedure for routine use. The method is relatively rapidwill detect minor components of mixed calculi and canreadily be made quantitative.2

At present there is no single analytical procedure thatwill provide an exact quantitative analysis of urinarycalculi. In the present procedure it is assumed that onlycalcium oxalate monohydrate, hydroxyapatite, ormagnesium ammonium phosphate hexa hydrate arepresent. Although the monohydrate is the commonestform of calcium oxalate in urinary calculi.3 Some stones

contain appreciable quantities of the dihydrate and insuch cases the present assumptions will result in an underestimation of the amount of calcium oxalate present. Afurther possible source of error is that calcium andphosphate may be present as brushite (CaHPO4-2H2)),Whitlockite (âCa3 (PO4) 2) Octacalcium phosphate(Ca8H2 (PO4) 6. 5H2O), while magnesium may be presentas newberyite (Mg H PO4. 3H2O). However, theseminerals are usually present only as minor componentsso that errors from these sources are probably small.2

The nomenclature used in this study to identify stonecomposition was designed to identify the actual chemicalmake up as well as the specific crystalline componentsof each stone. The chemistry of a stone is a reflection ofwhat chemical groups or moieties are available in theurine at the time of formation and growth of the stone.

MATERIALS AND METHODS

Urinary calculi of 100 patients of kidney stone werecollected and analysed quantitatively statistical analysiswas done through SPSS 12 software. Student’s t testwas applied wherever necessary.

The stone was powdered in a pestle and mortar. Themain elements and radicles of interest are calcium,magnesium, inorganic phosphate, uric acid and oxalate.

Original Article Nepal Med Coll J 2010; 12(3): 145-148

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From knowledge of these constituents it is possible to calculatethe composition of a stone in terms of calcium oxalate, calciumphosphate, and magnesium ammonium phosphate.

The procedure was followed as per Hodgkinson A.2

Dissolve 20 mg of powdered stone in 2 ml of 50 % (V/V) HCl, with warming, and dilute to 10 ml with waterin a volumetric flask (Solution A). This solution is usedfor all the subsequent determinations. The stone solutionstored at 2-8o C when not in use.

RA-50 Chemistry analyser was used for the estimationof Calcium by Trinder’s method,4 inorganic phosphateby Fiske and subbaraw method, 5 uric acid by Caraway’smethod, 6 magnesium by Neil and Neely method7 can bedetermined by standard procedures.

The oxalate radicle can also be determined by a simplepermanganate titration.8

Estimation of oxalate

Procedure: Mix 1 ml of the dissolved stone (SolutionA) with 2 ml of 2 N H2SO4. Add one drop of an aqueoussolution of 5.0% (W/V) MnSO4, heat to between 70 and800C, and titrate rapidly with standard 0.01 N KMnO4till persistent pink colour end point.

A ‘control’ sample of powdered calcium oxalate (20 mg)when treated in a same manner should give a recoveryof 99 to 100 % after allowing for titration blanks (1 mlof 0.01 N KMnO4 is equivalent to 0.45 mg of oxalicacid). Accuracy of experiment was confirmed byrecovery experiment.

Calculations1) One ml of 0.01 N KMnO4 is equivalent to 0.45 mg ofoxalic acid.

The mechanism of the reaction between oxalate andpermanganate is complex. The first few drops of

permanganate react slowly withoxalic acid but after a small amountof manganous salt has been formedthe reaction occurs almostinstantaneously in hot solution. Themanganous ions appear to catalysethe reaction between permanganateand oxalic acid and the addition of adrop of MnSO4 solution thereforeensures a sharp endpoint from thestart of the titration. ManganousSulphate serves a double purposesince it also prevents any reactionbetween permanganate andhydrochloric acid.

2) The percentage composition of a stone in terms ofcalcium oxalate, magnesium ammonium phosphate, uricacid, hydroxsyapatite can be calculated from thefollowing equations: -

1. Calcium oxalate monohydrate = Oxalic acid (gramsof anhydrous acid per 100 gm of calculus) × 1.62

2. Magnesium ammonium phosphate hexahydrate =Magnesium (grams per 100 gm of calculus) × 10.2

3. Hydroxyapatite (Ca10 (PO4) 6 (OH) 2)= Magnesium ammonium phosphate × 31

247.3= Phosphate in Magnesium ammonium hexahydrate.Hydroxyapatite = (total phosphate (grams per 100 gm

of calculus) – Phosphate in Magnesium ammoniumphosphate hexahydrate) × 5.4

4. A = The total calcium contained in calcium oxalatemonohydrate

= Calcium Oxalate × 40 146.12

B = The total calcium contained in Hydroxyapatite= Hydroxyapatite × 400

1004.·. Total calcium contained in calculus = A + B5. Uric acid = Uric acid × 100

20

RESULTS

The Hydroxy apatite calcium oxalate and uric acid stonesare commonly observed stones in this area revealed byTable-1.

Using the present procedures it was possible to accountfor 90.0% ± 5.0% of the total weight of most stones,the remainder was accounted for mainly by water andprotein.

Nepal Medical College Journal

Table-1: Showing percent composition of stone Stone analysisParameters Means ± SDOxalic acid 20.35 ± 10.70 (g anhydrous/100g calculus)Magnesium 0.33 ± 0.65 (g / 100 g calculus )Inorganic Phosphate 8.09 ± 3.08 (g P / 100 g calculus)Calcium oxalate monohydrate 32.84 ± 17.28 (Equation I)Magnesium Ammonium phosphate 3.33 ± 6.66 (Equation II)Hydroxy apatite 41.70 ± 16.56 (g / 100 g calculus )Total Calcium (Calculated) 25.68 ± 5.38Total calcium (Found) 25.58 ± 5.25Uric acid 27.12 ± 11.42Total content 87.24 ± 5.93

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Human urinary stones generally contain more than onetype of crystals and there is a tendency for certain crystalsto occur together. Calcium oxalate and calciumphosphate are the two most common components ofurinary stones. Fig. 1. shows calcium is the mostcommon major component of the stones. The totalcalcium found by analysis of 100 stones is 25.68 ±5.38.Calcium oxalate hydrate is the most commoncrystal present is 32.84 ± 17.28, which contains oxalicacid 20.35 ± 10.70. Apatite is the second most commoncrystal found 41.70 ± 16.56 contains inorganic phosphate8.09 ± 3.08. CaOX / apatite is the most commoncombination.

In case of uric acid stones it is present in combinationwith CaOX and CaP. Total uric acid found in these stonesis 27.12 ± 11.42.

In case of magnesium ammonium phosphate (MAPH)is present in combination of CaOX and CaP. MAPH is3.33 ± 6.66 magnesium present is 0.33 ± 0.65. All stonescontains a organic matrix. The percentage present asorganic matrix in stones varied from 2.0-30.0%.

A statistical analysis performed on 100 urinary calculishowed the following distribution, with regard to themajor component are calcium oxalate 32.8% (combinedmonohydrate and dihydrate), Phosphate 41.7%,Magnesium ammonium phosphate hexahydrate 3.3%and uric acid 27.1%.

DISCUSSION

Urinary calculi are formed as a result of a biologicalmaladjustment of urine. The stone formation is attributedto supersaturation of urine and retention of solidparticles.Its composition varies from being homogeneous(from the nucleus to the periphery) to heterogeneous.Thislatter state results from successive and differentaggregations and crystal growths due to various diets.9

For diagnosis, understanding of etiology and treatmentof lithiasis, it will be necessary to characterize and analyze

the ions and moleculesparticipating in the formation ofurinary calculi. The purpose of thisstudy was to quantify hydrateforms of calcium oxalate (COMand COD) in calcium oxalatestones, calculi containing uric acidor magnesium ammoniumphosphate hexahydrate (MAPH).

Our results showed the presenceof calcium oxalate in all stones.Although calcium oxalate becauseof its high solubility is the most

common component of renal calculi, its presence in99.8% of the stones analyzed. The majority of renalcalcium stones contains mixtures of calcium oxalate andcalcium phosphates, and it is evident that theprecipitation of calcium oxalate is fundamental for theformation of these stones. A pure calcium phosphatestone was unusual.

Among the urinary calculi studied, several ones consistedof pure calcium oxalate hydrate and uric acid wereobserved, where as some consisted of calcium oxalatehydrate was associated with free water, organic matterand variable amounts of calcium phophate. In case ofuric acid stones, uric acid can be presented in mixtureswith calcium oxalate hydrate, free water and organicmatter. In case of magnesium ammonium phosphatehexahydrate (MAPH), obtained mixture of calciumoxalate hydrate, organic matter and calcium phosphate.

The mixture calcium oxalate hydrate / uric acid / MAPHhas never been observed. Calcium phosphates are oftenpresent in oxalate stones. Calcium phosphate was presentin more than 80.0% of calcium oxalate calculi. All stonescontains a second principal component, referred as organicmatrix (albumins, proteins, non amino sugars, nitrogenand water being major constituents). The percentage bymass of the organic matrix (as a percentage of the originalmass) varied from 2.0-20.0% but with a mean of 2.5%.

Calcium carbonate and cystine was not component ofany stone analyzed. Absence of cystine was confirmedby chromatography.

Using the present procedures it was possible to account for90.0% ± 5.0% of the total weight of most stones; theremainder was accounted for mainly by water and protein.10

We have used the quantitative procedure for the analysisof 100 urinary calculi and it has been found to be reliableand suitable for routine use. Moreover it requires onlyapparatus, which is currently available in most modernhospital laboratories.

S Jawalekar et al

Fig.1 Chemical composition of various stones in renal calcius subjects

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ACKNOWLEDGEMENTSWe are thankful to Department of Urology, A.C.P.M. MedicalCollege, Dhule for giving permission to carry out research.We are also thankful to medical superintendent of A.C.P.M.Medical College, Dhule for seeking clinical material involvedfor this study purpose.

REFERENCES

1. Pollack SS, Carlson GL. A comparison of X-ray diffractionand infrared technics for indentifying kidney stones. Amer JClin Pathol 1969; 52: 656-60.

2. Hodgkinson. A combined qualitative and quantitativeprocedure for the chemical analysis of urinary calculi. J ClinPathol 1971; 24: 147-51.

3. Sutor DJ, Wooley SE, Illingworth JJ. Some aspects of theadult urinary stone problem in Great Britain and NorthernIreland. Brit J Urol 1974; 46: 275-88.


4. Trinders P. Colorimetric microdetermination of calcium inserum. Analyst 1960; 85: 889-94.

5. Fiske CH, Subbarow Y. The colorimetric determination ofphosphorus. J Biol Chem 1925; 66: 375-400.

6. Caraway W T: Determination of uric acid in serum by acarbonate method. Amer J Clin Pathol 1955; 25: 840.

7. Neil W, Neely RA .Titan yellow method for magnesium. JClin Pathol 1956; 9: 162.

8. Baxter GP, Zanetti JE. The determination of oxalic acid bypermanganate in the in the presence of hydrochloride acid.Amer Chem J 1905; 33: 500-6.

9. Jungers P, Daudon M, Le Due A. Lithiase urinaire.Paris:Flanmarion Medecine sciences.1989.

10. Hodgkinson A, Peacock M, and Nicholson M. Quantitativeanalysis of calcium- Containing urinary calculi. Invest Urol1969; 6: 549-61.

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Long term effects of monosodium glutamate on spermatogenesisfollowing neonatal exposure in albino mice – a histological study

RS Das1 and SK Ghosh2

Department of Anatomy, 1Agartala Govt. Medical College, Kunjavan, Agartala, Tripura, India,2Nepal Medical College, Jorpati, Kathmandu, Nepal

Corresponding author: Dr. Rajat Subhra Das. MS (Anatomy), Asst Prof, Dept of Anatomy, Agartala Govt Medical College,Kunjavan, Agartala, Tripura, India: 799006; e-mail: [email protected]

ABSTRACT

Monosodium glutamate (MSG), popularly known as Azinomoto has been in use since long as a flavour enhancingsubstance. Its widespread use has also earned it a bad name as hazardous for human health. It has beenincriminated to cause wide range of effects comprising retinal degeneration, metabolic disorders, endocrinaldisorders including reduced fertility rate in both male and female experimental mice and rats following neonatalexposure. However there are many contradicting views too regarding the above effects which have promptedus to undertake the present study. In our study seven newborns of Swiss Albino mice were injected subcutaneouslywith MSG (2mg / gm of body wt. in a dilution 40 mg of per ml. of distilled water) on completion of 2nd, 4th,6th, 8th and 10th day of life. Similar number of controls were injected with same volume of distilled water.Testes were obtained through dissection on completion of 75 days of life. 5 micron thick sections were cut,stained by H.E. and Heidenhain’s Iron Haematoxylin and studied under light microscope. It was observed fromthe quantitative analysis of the seminiferous tubules that there was increase in the number of the pachytenestage of primary spermatocyte in the experimental group as compared to that of the control animals ofcorresponding age.Keywords: Monosodium glutamate (MSG), swiss albino mice, testes, primary spermatocyte (pachytene stage).

INTRODUCTION

Monosodium glutamate (Azinomoto) is a well knownfood additive used throughout the world. This flavourenhancer, not very long ago, was isolated in thelaboratory, is called Monosodium Glutamate (MSG) Ata later stage this flavour gained immense popularityworldwide. Since then it has been in use, widely inrestaurants (particularly mixed in noodles, soups etc.),packaged food industries (eg. instant meals) andhousehold kitchens. Modern commercial MSG isproduced by fermentation of starch, sugar, beet,sugarcane or molasses.1

MSG’s great property of enhancing the taste of thefood and overwhelming popularity prompted theScientists to analyse its possible effects in human. Since1960s, the research data began to show dangers of MSG,though, differences in observations surfaced from timeto time. The experimental animals showed some adverseeffects. At the same time, the experiments showed thatthe neonates of mice were the most sensitive of allanimals.2 These effects involved the central nervoussystem, retina, endocrine glands including gonadsetc.The hypothalamus, particularly its arcuate andpreoptic nuclei developed lesions following exposureof the experimental animals to MSG during neonatalperiod.3

There were several studies in respect of the effect ofMSG in the tissues related to the reproduction eg. testis,ovary, uterus etc,. in the neonatal animals (rats, mice),following exposure to MSG (dose varying from 2.2 to 4mg / kg of body wt.). Though there were reduction inweight of testes and ovaries, the former did not showany changes on histological aspect. Fertility rate hadbeen reported to be reduced in both sexes,4 or in malesonly.5 However, we couldn’t get any literature regardingthe histological studies of the testes following neonataltreatment of animals with MSG.Hence we have embarked on this journey v to study thehistological changes in the testes, in neonate mice.Biochemical aspect: This compound MSG is a salt ofsodium and (L -) Glutamic acid. In pure form it appearsas a crystalline powder. L – Glutamic acid is anubiquitous amino acid present in most foods either inthe free form or bound to peptides or proteins. It hasbeen calculated that in a 70 kg man has a daily Glutamicacid (GA) intake of ~ 28 gm that is derived from thediet and rest from the breakdown of gut proteins. Thedaily GA turnover in the body is ~ 48 gm. Despite thislarge turnover, the total pool of GA in blood is quitesmall, ~ 20 gm, because of its rapid extraction from andutilization by various tissues, particularly muscle andliver.6


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Today, it is widely accepted that GA is the majorexcitatory neurotransmitter within the brain, mediatingfast synaptic transmission and active in perhaps one thirdof all CNS synapses.7


In this study, the newborn pups of the Swiss – Albinomice were selected as the animal model.

Summary of the procedure – The neonates were exposedto natural day and night sequence, each on 12 hours basis.The animals were divided into two groups, Group A(Experimental) and Group B (Control). Each group wasfurther subdivided on the basis of the date of birth of thelitters of each mother. The design of the study is shownin Table-1.

A stock solution of injection was prepared by dissolv-ing 4gm of MSG crystals in 100 ml of distilled water(D.W.) so that 0.05 ml of the said solution contained 2


Control group Experimental groupMean birth wt. - 1.43 gm 1.49 gmMean body wt. on 28th day 11.66 gm 13.38 gmMean body wt. on 75th day 26.82 gm 27.9 gmMean birth -wt. - 1.49 gmMean body wt. on 28th day 13.38 gmMean body wt. on 75th day 27.9 gm

Table-2: The weight of the pups of both the groups on 28th

and 75th days

mg of MSG. The doseschedule was so adjustedthat the amount of MSGinjected per pup as pertheir respective weight.

Procedure forinjection to theexperimental group -The newborns of theExperimental group weregiven the subcutaneousinjection of MonosodiumGlutamate ( MSG ) at thedose of 2 mg / gm(8) ofbody weight on day 2, 4,6, 8 and 10 of postnatal lifethrough insulin syringeafter weighing each pup onthose respective days andcalculating the doseaccordingly. Thenewborns of the Controlgroup were given

corresponding volume of distilled water for injection onsimilar scheduled days of postnatal life.

General Observations: All the animals were examinedfor any gross abnormalities or changes eg. generalappearance, condition of skin and fur, structural defectsetc. The weight of the pups were taken on 28 and 75 dayafter birth. After the testes were dissected there volumewere majored by water displacement method.

Histological study: At two and half months of age ofthe aninmals were sacrificed after anaesthetizing withinjection of Thiopentone sodium given intraperitoneallyin a dose of 50 mg / kg of body wt. Prior to dissection,perfusion was carried out with 10 ml solution of Formalsaline (10.0%) through intracardiac catheterization . Thetestes were collected from respective animals dried thenweighed, and volume of each was measured. The testisof one side of each animal were ly immersed in 10%formal saline while that of the other side were put inZenker – Formol (Helly’s Fluid ) solution and the tissueswere processed accordingly.8

Quantitative and qualitative assessment -

The present investigation was aimed at quantitativeassessment of the seminiferous tubules. In case of thetestis the parameters being the tubular diameter, volumeproportion of the tubules and count of pachytene stageof the primary spermatocyte (as an index ofspermatogenesis).9 To estimate these stereology andmorphometrical methods were used.

Table-1: Study design of annual experimentParticulars Group A (Experimental) Group B (Control)1) Weight of the pups Weighing of each neonate of both group was done before drug administration2) No. of neonates Male – 7 Male – 53) Administration of dose. Monosodium glutamate dissolved in Littermate control was injected

distilled water (for injection) was with same amount of distilledinjected subcutaneously (s.c.) on water s.c. on same days ofcompletion of 2, 4, 6, 8 and 10 days postnatal life like that of theof life through disposable insulin experimental group.syringe and needle.

4) Nursing and rearing Neonates of both group (Expt. And Control) were kept with their damstill 27 th day. On 28 th day, the pups were separated from their motherand they were segregated on sex basis and they were given rat feed andwater ad libitum.

5) Histological study At two and half months of age 7 nos. of male from Group A (Expt. ) and5 nos. of male from Group B ( Control ) were sacrificed after administering Inj. Thiopentone Sodium intraperitoneally. Following dissection,the testes were collected and weighed and volume was measured.Tissueswere processed for routine paraffin embedding and 5 micron thicksections were cut and stained with H & E and Heidenhens ironhaematixylin stain. Stained sections were studied under light microscopy.

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Five tubules from each section were considered.Everyfifth section were studied.Total number of twenty tubuleswere studied for each animal.

Testicular histological study -

(a) Volume proportion of the tubule:Thus the volume proportion of the components “tubule”were calculated by superimposing Haug’s graticule grid,randomly and repeatedly and subsequently counting thenumber of points which fall on the tubule. The volumeproportion will thus be,

p = h / (h + m)where, p is the volume proportion component, h is thenumber of points falling on the component and m is thenumber of points falling elsewhere.

(b) Volume of the testes:(c) Diameter of the seminiferous tubule – it is measured

by recording the shortest distance two diametricallyopposite points on the border between basementmembrane and germinal epithelium.9 We did it byprojecting the tubule on the screen of the Ermascope202 and then measured with the help of eyeipiecemicrometer, standardized by projecting on the stagemicrometer before calculation. The total number of20 tubules from five sections of each animal weretaken for consideration in both control andexperimental animals.

(d) Measurement of the tubular area and Nuclei count –Measurement of the tubular area was done with thehelp of the ‘hit method’.9 To gain an impression ofspermatogenetic activity, we considered only thepachytene spermatocytes.9 These cells stands outbecause it is present in almost every spermatogeniccycle and its characteristic nucleas and size were

unmistakable. The nuclear count of pachytenespermatocytes were regarded as a criterion of theregenerative capacity of the germinal epithelium.

Statistical analysis: We analysed the data with the helpof Student’s t - test (un-paired).10

OBSERVATION:

A. Gross observations – 5 male pups born out of 2 (two)females (female pups born were excluded) on differentdates were selected as Control group (Group B). All thepups survived throughout the period of experiment. Wecollected the required tissues by performing thedissection on scheduled dates. In the second set ofexperiment, 7 male pups born out of 3 (three) mothers(female pups born were excluded) on different datesreceived MSG injection as per schedule and kept asExperimental group (Group A). However there were nocasualties in these group also.

The pups of either group did not show any externalabnormalities at birth. The average hair growth and eyeopening were recorded on 7 days and 10 daysrespectively. The nutritional effect of MSG on the pups(if any) were gauged by the gain in weights. In thiscontext we measured the weight of the pups at birth, on28 th day and on 75 th day. The weights measured foranimals of each group were put in tabulated form (Table-1). There were increase in the weight of the experimentalgroup of pups. Mean body weight of control group were26.8 gm and those of experimental group was 27.9 gm(75 days) Table-2.

B. Weight and volume of testis – The weight and volume ofthe each gonad were measured and the data were tabulated.There were not much difference in the mean weight andvolume of the testes of two groups of animals (Table-3).

Histology of testes of control group – The lightmicroscopic study was carried out. The tubules were ofdifferent shapes in the cross sections. Individual tubulewas surrounded by interstitial connective tissue withcapillary network and interstitial cells. When the cellularconstituents of the tubules were studied we observedmostly three different spermatogenic cellularassociations according to the cell cycle. The morefrequent one seen was consisting of spermatogonia (darkand pale types), 2 to 3 layers of primary spermatocytesat different stages of division, mostly at the pachytenestage, several layers of spermatids and spermatozoon.The second cellular association were seen consisting ofspermatogonia, several layers of primary spermatocyteand spermatids, and immature spermatozoa withelongated head and residual cytoplasm at the other end.

Nuclei of few sertoli cells in each of the tubule were seen.

RS Das et al

Group No. of Average Volume Average Weight ofanimals of testes (cc) testes (gm)

Control 5 0.1 93.4Experimental 7 0.1 93.2Significance P > 0.05, NS P > 0.05, NS

Table-3: Mean of the volume and body wt. of the testes ofthe Control and MSG treated mice at autopsy (i.e.75th day).

Table-4: Measurements of the diameter of theseminiferous tubules

Group No. of No. of the tubules Mean diameter Standard Significanceanimals observed @ 20 (in micron) deviation (one tailed

tubules per animal (SD) student’st-test)

Control 5 100 196.24 P > 0.05i.e. NS

Experimental 7 140 193.46 14.94

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The nucleus appeared very pale and irregular outline, somewith a centrally placed nucleolus. The nuclei were locatedaway from the basement membrane. The interstitial tissuebetween the tubules contained connective tissue withcapillaries and clumps of interstitial cells (Leydig cells).The cells were ellipsoidal with oval nuclei. The cytoplasmlooked vacuolated, but strongly eosinophilic. The cellswere grouped around capillaries.

Testes in Experimental Group – Tubules were cut indifferent cross sectional view. Different types ofspermatogonia cells were seen. The diameter of the tubuleswere of different size in the same section similar to thatof Control animals. The spermatogenic cells were severallayers thick but lesser than that of Control animals. Theywere little dissociated and disarrayed, though cellularassociations like that of the control group were seen. Even,spermatozoa with well formed tail were seen in the lumenof some tubules. But most important observation withinthe tubules were that of increased number of pachytenestage of primary spermatocyte. The interstitial cellsappeared to be more in number and larger than that of thecontrol animals. They were round to oval, with oval nucleiand vacuolated eosinophilic cytoplasm.

Quantitative assessment of testes: The quantitativerecord is an important evulationary guide for definingthe functional status of the testis. We have selected thefollowing parameters eg. diameter of the tubules, areaof the tubules and number of pachytene stage of thespermatocytes per tubule. The comprehensivequantitative data along with statistical analysis werepresented in (Table 4-6).

DISCUSSION

No sooner had MSG earned world wide popularity italso started earning bad names. Studies and experimentscarried out in different animal model using different doseschedule, administered through different routes e.g. oral,parenteral etc. We used mice because of severaladvantages eg. easy handling and availability, continuousreproductive cycle independent of seoson,reproducibility of the experiments owing to shortreproductive cycle etc. Studies also established that miceis one of the most susceptible species to the MSG. Thesimilar pattern of experiment were conducted byothers.2,11

We performed this experiment with 2 mg/gmof body weight of MSG administeredsubcutaneously (s.c.) on alternate day startingfrom 2 nd day of neonatal life (48 hr.) for 5days. Others had used different dose schedule,mostly a gradually increasing dose over thedays. Olney3 used the dose of 2.2 mg to 4.2mg/gm of body wt. in a gradually increasing

dose administered through s.c. route from day 2 to day11 of the neonatal life of the mice. Same schedule wasalso followed by others.4,12,13 While the first author4 usedinfant mice, the other two authors12,13 used infant rat asanimal model. Few authors14,15 used an alternate dayregime in a dose of 4 mg/gm given to the neonates ofthe rats, we however, adopted the uniform dose at theminimum level. In the present study pups getting MSGat a dose of 2 mg/gm of body wt survived through theperiod of observation while Diniz et al16 opined that dailydietary intake of man from reasonably all possiblesources did not exceed more than 0.7gm i.e. 0.01 mg/gm of body wt. in an average adult. They further addedthat infant mice were not equipped with enzymes tometabolise MSG. According to them this dose of 2 mg/gm of body wt. introduced in infant mice was comparableto about 6 gm in human infant. It was observed that twoweek old mice usually convulsed to death from s.c. dosesbetween 5 – 6 mg/gm of body wt. but this dose in 1 dayold infant mice was readily lethal without convulsion.3

In the present study the pups received MSG at a dose of2mg/gm of body wt survived through the observation.The dose schedule followed by us was much lower thanthat of experiment conducted by the others.3,4,12,13

We observed that the grown up pups of the MSG treatedgroup gained more weight than that of the controlanimals which might be due to higher voluntary intakeof food, because of neuroendocrinal disturbance. Similarfinding were reported by other authors.3,17

In the present experiment we studied the histology ofthe testes after H & E staining for general histology,Heidenhain’s iron haematoxylin staining for nucleus, theH & E stained sections of the testes of the experimentalgroup showed tubules apparently similar in size as thatof the control animals. We noticed three types of cellularassociations in both groups of animals. In one of the


Table-5: Measurements of the area of the seminiferous tubulesGroup No. of No. of the tubules Mean diameter Standard Significance

animals observed @ 20 (in micron) deviation (one tailedtubules per animal (SD) student’s t-test)

Control 5 100 0.0285 0.0302 P > 0.05i.e.NS

Experimental 7 140 0.0277

Table-6: Nuclear count per unit of the seminiferous tubulesGroup No. of No. of the tubules Mean diameter Standard Significance

animals observed @ 20 (in micron) deviation (one tailedtubules per animal (SD) student’s

t-test)Control 5 100 256.4 43.56 P > 0.05 i.e.

SignificantExperimental 7 140 364.26

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cellular associations we noticed spermatogonial layer,resting stage of primary spermatocyte and spermatidswhile the other had the spermatogonial layer, pachytenestage of primary spermatocyte, spermatids and maturingspermatozoa with residual cytoplasm. In many of thetubules of the experimental group the layers of cells ofthe spermatogenic epithelium were less. Interestinglywe observed that the pachytene stage of primaryspermatocytes appeared to be more and the interstitialcells (Leydig cells) were larger in testicular sections ofthe experimental group compared to that of control.However, we could not find any literature describingdetail histological features of testes in MSG treated micehence these finding could not be compared. We alsoassessed the seminiferous tubules quantitatively eg.diameter and area of the tubules in a section, no. of thepachytene stage of primary spermatocyte in the tubules.There were little difference in the diameter of the tubulesbetween control group and the experimental group. Themean diameter of experimental group were little less,though they were not statistically significant. (196.24micron and 193.46 micron respectively). However therewas a significant finding of increased no. of thepachytene stage of primary spermatocyte (Table-5) inthe tubules of the experimental group (364.26/unit areain experimental group compared to that of 256.4/unitarea of control group). The significant increase in thepachytene spermatocyte with attenuated layer possiblysuggested compensatory mechanism for the more lossof speramtogenic cells in the experimental group.

The enlarged size of the Leydig cells observed in case ofthe testes of the experimental group might be due tocompensatory hypertrophy since testosterone level showeda decreased l in MSG treated males.15 No other workercommented on the size and number of the Leydig cells.

Summary: Our observation of MSG inducedhistological changes in the testes showed that both thegerminal epithelium and Leydig cells were affected.There was fewer spermatogenic cells in many of thetubules with significantly increased pachytene stage ofprimary spermatocytes. The Leydig cells werehypertrophied. This was possibly due to disruption ofthe pituitary-adrenal axis leading to low serum LH andtestosterone level. As reported by some authors,testosterone level showed a decreased level in MSGtreated males.15,17

Different agencies tried to evaluate the safety aspect ofMSG in respect of human health along with other foodadditives. Joint FAO/WHO expert committee on foodadditives on 1988 has recognized MSG as generally safefor human consumption.1 From our observation we

conclude that MSG in the dose schedule used by us ininfant mice caused minor changes in seminiferousepithelium e.g increase in the pachytene stage of primaryspermatocytes, apparent increases of Leydig cells andalso gain in weight of the pups. These suggest somedamage to the seminiferous tubule by use of MSG andits long term effect should be evaluated further.

ACKNOWLEDGEMENTSThe authors thank Prof. A.K.Pal, (Human Genetics) and Dr. A.M.Tarneker, Assoc. Prof., Dep’t. of Anatomy, M.G.I.M.S., Sewagram,Wardha, Maharashtra for their advice and active support.

REFERENCES

1. Walker R, Lupien JR. The safety evaluation of monosodiumglutamate. J Nutr 2000; 130: 1049S-52S.

2. Garattini S. Glutamic acid, twenty years later. J Nutr 2000;130: 901S-9S.

3. Olney JW. Brain lesions, obesity and other disturbances in micetreated with monosodium glutamate. Sci 1969; 164: 719-21.

4. Pizzi WJ, Barnhart JE. Monosodium glutamate administrationof newborn reduces reproductive ability in female and malemice. Sci 1977; 196: 452-4.

5. Bakke JL, Lawrence N, Bennett N, Robinson S, Bowers CY.Late endocrine effects of administering monosodium glutamateto neonatal rats. Neuroendocrinol 1978; 26: 220-8.

6. Munro HN. Factors in the regulation of glutamate metabolism.Glutamic acid - Advances in Biochemistry, 1979; 55-68(Raven Press New York, NY).

7. Watkins JC, Evans RH. Excitatory amino acid transmitters.Annu Rev Pharmacol Toxicol 1981; 21: 165-204.

8. Drury RAB, Wallington EA. Carleton’s HistologicalTechnique. 1980; 5th edn., Oxford University Press: 438-49.

9. Weissbach L, Ibach B. Quantitative parameters for lightmicroscopic assessment of the tubuli seminiferi. Fertil Steril1976; 27: 836-47.

10. Mahajan BK. Methods in biostatistics for medical studentsand research workers, 1997 (6th edn.), Jaypee Brothers(publishers): 141-5.

11. Chatterjee TK. Handbook of laboratory mice and rats. 1993;1st edn, Calcutta: 3-8.

12. Redding TW, Scally AV, Arimura A. Effect of MonosodiumGlutamate on some endocrine functions. Neuroendocrinol1971; 8: 245.

13. Trentini GP, Botticelli A, Botticelli CS. Effect of monosodiumglutamate on the endocrine glands and on the reproductivefunction of the rat. Fertil Steril 1974; 25: 478-83.

14. Rodriguez – Sierra JF, Sridaran R, Blake CA. MonosodiumGlutamate disruption of behavioral and endocrine functionin the female rat. Neuroendocrinol 1980; 31: 228-35.

15. Miskowiak B, Partyka M. Effects of neonatal treatment withmonoisodium glutamate on hypothalamo – pituitary – thyroidaxis in adult male rats. Histol Histopathol 1993; 8: 731-4.

16. Diniz YS, Faine LA, Galhardi CM, Novelli EL. Monosodiumglutamate in standard and high fiber diets: metabolic syndromeand oxidative stress in rats. Nutr 2005; 21: 749-55.

17. Sun YM, Hsu HK, Lue SI, Peng MT. Sex specific impairmentin sexual and ingestive behaviours of monosodium treatedrats. Physiol Behav 1991; 50: 873-80.

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Immediate effect of a slow pace breathing exercise Bhramari pranayamaon blood pressure and heart rate

T Pramanik, B Pudasaini and R PrajapatiDepartment of Physiology, Nepal Medical College, Jorpati, Kathmandu, Nepal

Corresponding author: Dr. Tapas Pramanik, Associate Professor, Department of Physiology, Nepal Medical College,Jorpati, Kathmandu, Nepal; e-mail: [email protected]

ABSTRACT

The study was carried out to evaluate the immediate effect Bhramari pranayama, a slow breathing exercise for5 minutes on heart rate and blood pressure. Heart rate and blood pressure of volunteers were recorded. Thesubject was directed to inhale slowly up to the maximum for about 5 seconds and then to exhale slowly up tothe maximum for about 15 sec keeping two thumbs on two external auditory canal, index and middle fingertogether on two closed eyes and ring finger on the two sides of the nose. During exhalation the subject mustchant the word “O-U-Mmmma” with a humming nasal sound mimicking the sound of a humming wasp, so thatthe laryngeal walls and the inner walls of the nostril mildly vibrate (Bhramari pranayama, respiratory rate 3/min). After 5 minutes of this exercise, the blood pressure and heart rate were recorded again. Both the systolicand diastolic blood pressure were found to be decreased with a slight fall in heart rate. Fall of diastolic pressureand mean pressure were significant. The result indicated that slow pace Bhramari pranayama for 5 minutes,induced parasympathetic dominance on cardiovascular system.Keywords: Bhramari pranayama, parasympathetic dominance.

INTRODUCTION

The cases of stress-related disease are increasing dayby day throughout the world and the World HealthOrganization (WHO) Global Burden of Disease Surveyestimates that mental disease, including stress-relateddisorders, will be the second leading cause of disabilityby the year 2020.1 Stress, is inevitable, but can becombated by many ways (e.g., adopting regular physicalexercise, change of lifestyle, change of food habit, etc.).2

According to many, yoga and pranayama (breathingexercises) can be practiced to combat stress.3,4 It has beenreported earlier that yoga and pranayama are beneficialfor the treatment of cardiopulmonary diseases,autonomic nervous system imbalances, and psychologicor stress-related disorders.3,5 Slow pranayamic breathingis reported as one of the most practical relaxationtechniques. Pranayama (breathing exercise) is knownas a part of yogic techniques followed in ancient India.Pranayama is defined as a manipulation of breathmovement. Different types of pranayamas producedifferent physiologic responses in normal youngvolunteers. Savitri pranayama, Kapalbhati, Bhasrika,Nadisnddhi pranayama, and so on are well knownamong them. 6 Most of the studies report the effect ofdifferent pranayamas, yogic postures, meditation, andso on collectively and the effect of regular practices ofall these for a period of time, (e.g., 1 month, 3 months,etc.). In the present study, the immediate effect of asimple breathing exercise (Bhramari pranayama) for 5

minutes’ duration on blood pressure and heart rate hasbeen represented.

SUBJECTS AND METHODS

Healthy, nonsmoker, sedentary volunteers (n = 50; male25, females 25; age 25–35 years) took part in this study.They were either medical students or staff of our medicalcollege. The aims and objectives were explained andverbal consent was taken. Heart rate was noted. Bloodpressure was recorded by using a mercurysphygmomanometer following 5 minutes rest.7,8 Thebreathing technique was demonstrated to them. First,one has to sit comfortably in an easy and steady posture(Sukhasana) on a fairly soft seat placed on the floor andkeeping the head, neck, and trunk erect and in a straightline, with eyes closed. One should keep the body stillduring the breathing practice. The back muscles shouldnot remain very stiff and he/she should try to keep theother muscles also loose. Then the subject was directedto inhale through both the nostrils slowly up to themaximum for about 5 sec. The breathing must not beabdominal. Then subject was instructed to exhale slowlyup to the maximum through both the nostrils for about15 sec keeping two thumbs on two external auditorycanal, index and middle finger together on two closedeyes and ring finger on the two sides of the nose. Duringexhalation the subject must chant the word “O-U-Mmmma” with a humming nasal sound mimicking thesound of a humming wasp, so that the laryngeal walls


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and the inner walls of thenostril mildly vibrate. Thesesteps complete one cycle ofBhramari (slow pace)pranayama (respiratory rate3/min)..9 The pranayamawas conducted in a cool,well-ventilated room (18–20°C). After 5 minutes ofthis breathing practice, theblood pressure and heartrate were recorded again inthe aforesaid manner usingthe same instrument. Datawas statistically analyzed byusing Student’s t test. Afterthe breathing exercise they were asked about theirfeeling.

RESULTS

In both the sexes slow Bhramari pranayamic breathing(respiratory rate 3/min) for 5 minutes caused a slightfall in heart rate. In male subjects heart rate wasdecreased from 78 beats/min to 76 beats/min and infemale volunteers the same was decreased from 82 beats/min to 79 beats/min. The systolic blood pressure alsodecreased. In male volunteers systolic blood pressuredecreased from 116 mm Hg to 111 mm Hg and in femalecounterpart systolic blood pressure decreased from 109mm Hg to 104 mm Hg following Bhramari pranayama.Whereas, the diastolic blood pressure and the meanpressure decreased significantly. In male subjectsdiastolic pressure decreased from 79.36 mm Hg to 72.88mmHg; in female volunteers the same decreased from73.60 mm Hg to 69.44 mm Hg. Mean pressure in maleand female volunteers decreased from 91.51 mmHg to85.51mmHg and 85.40 mmHg to 81.46 mmHgrespectively (Table-1 and Fig. 1). After the breathingexercise some felt calm; some felt sleepy; some felt verylight and calm.

DISCUSSION

The Sanskrit word Bhramar means wasp. As in thisPranayama the humming sound of a flying wasp is

mimicked, it is named as Bhramari pranayama. Thatslow pace pranayama influence the heart rate and bloodpressure through the parasympathetic dominance hadbeen reported in our previous study.10 As Bhramaripranayama is a type of slow pace breathing exercise, itstimulates the parasympathetic system. Earlier studiesalso reported that Bhramari pranayama producedgamma wave indicating parasympathetic dominance.11

Pranayama increases frequency and duration of inhibitoryneural impulses by activating stretch receptors of the lungsduring above tidal volume inhalation as in Hering-Breuerreflex.12 Inhibitory impulses, produced by slowly adaptingreceptors in the lungs during inflation13 play a role incontrolling typically autonomic functions such as systemicvascular resistance and heart rate.14

Inhibitory current synchronizes rhythmic cellular activitybetween the cardiopulmonary center15 and the centralnervous system.16 Inhibitory current regulatesexcitability of nervous tissue17 and is known to elicitsynchronization of neural elements, which typically isindicative of a state of relaxation.18 Synchronizationwithin the hypothalamus and the brainstem19 is likelyresponsible for inducing the parasympathetic response20

during breathing exercises.

Diastolic blood pressure depends upon peripheralresistance, and lung inflation has been known to decrease

T Pramanik et al

* = p<0.05

Volunteers Systolic Blood pressure Diastolic Blood pressure Mean pressure(mm Hg) Heart rate(cycles/min.)(mm Hg) (Mean ± SD) (mm Hg)(Mean ± SD) (Mean ± SD) (Mean ± SD)Before After Before After Before After Before AfterBhramari Bhramari Bhramari Bhramari Bhramari Bhramari Bhramari Bhramari

Male (n=25) 115.84±12.15 110.80±13.30 79.36±9.12 72.88*±8.73 91.51±9.31 85.51*±9.10 77.92±16.88 75.68±14.86Female (n= 25) 109.04±9.40 104.32±8.59 73.60±6.05 69.44*±6.28 85.40±6.35 81.46*±6.32 81.60±12.31 78.96±11.73

Table-1: Effect of Bhramari Pranayama (5min) on blood pressure and heart rate

Fig. 1. Effect of Bhramari Pranayama (5min) on blood pressure and heart rate

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systemic vascular resistance.21 This response is initiatedby pulmonary stretch receptors, which bring aboutwithdrawal of sympathetic tone in the skeletal muscleblood vessels, leading to widespread vasodilatations,thus causing a decrease in peripheral resistance22 anddecreasing the diastolic as well as the mean bloodpressure in both the sexes in our study.

Vibration of the nasal /laryngeal mucous membraneduring exhalation along with the humming of “O-U-Mmmma” caused reflex apnoea by switching offinspiratory centre which causes bradycardia throughchemoreceptor sinu-aortic mechanism.23

During prolonged voluntary expiration intra-thoracicpressure increases and blood from the lungs is squeezedinto the heart leading to an increase in stroke volume;baro-receptors in carotid sinus experiences morepressure and discharge more. The increased baro-receptor discharge inhibit the tonic discharge of thevasoconstrictor nerves and excites the vagus innervationsof the heart producing vasodilatation, a drop in bloodpressure and bradycardia. 24

Vagal cardiac and pulmonary mechanisms are linked,and there are reasons to expect that improvement in onevagal limb might spill over into the other. It has beensuggested that chronic biofeedback-induced increasesin baroreceptor gain reflect neuroplasticity.25

Baroreceptor sensitivity can be enhanced significantlyby slow breathing. This seems to occur through a relativeincrease in vagal activity, as could be argued by the smallreduction in the heart rate observed during slowbreathing and by reduction in both systolic and diastolicpressure.26 Decrease in diastolic pressure was sosignificant that as a result mean blood pressure alsodecreased significantly.

Most of the volunteers felt calmness of mind, a sense ofwell-being, and some felt sleepy, thus supportingparasympathetic stimulation. This may be the effect ofincreased melatonin production after a regimen of slowbreathing pranayamic exercises.5 Slow pranayamicbreathing was also reported to elicit alpha waves,indicating a parasympathetic dominance27 and may bethe cause of the sleepy feeling.

Slow-pace Bhramari pranayama (respiratory rate 3/min) exercise thus shows a strong tendency of improvingor balancing the autonomic nervous system throughenhanced activation of the parasympathetic system andthus can be practiced for mental relaxation and reductionof stress of daily life.

ACKNOWLEDGEMENTSAuthors are thankful to the Head, Prof. P Roychowdhury andthe members of the Department of Physiology for their kind

cooperation and supports. We are grateful to the Principal ofNepal Medical College for allowing us to carry out the studyand support.

REFERENCES

1. Murray CJL, Lopez AD. The global burden of disease: acomprehensive assessment of mortality and disability fromdiseases, injuries and risk factors in 1990 and projected to2020. Report on behalf of the WHO and World Bank,Cambridge: Harvard University Press; 1996.

2. Madanmohan Udupa K, Bhavanani AB, Shatapathy CC, SahaiA. Modulation of cardiovascular response to exercise by yogatraining. Indian J Physiol Pharmacol 2004; 48: 461-5.

3. Brown RP Gerbarg PL. Sudarshan Kriya yogic breathing inthe treatment of stress, anxiety and depression: Part I.Neurophysiological model. J Altern Complement Med 2005;11: 189-201.

4. Bhattacharya S, Pandey US, Verma NS. Improvement inoxidative status with yogic breathing in young healthy males.Indian J Physiol Pharmacol 2002; 46: 349-54.

5. Harinath K, Malhotra AS, Pal K et al. Effects of hatha yogaand omkar meditation on cardio-respiratory performance,psychologic profile and melatonin secretion. J AlternComplement Med 2004; 10: 161-8.

6. Dhungel KU, Malhotra V, Sarkar D, Prajapati R. Effect ofalternative nostril breathing on cardio-respiratory functions.Nepal Med Coll J 2008; 10: 25-7.

7. Garg J, Messerli AW, Barkis GL. Evaluation and treatmentof patients with hypertension. Circulation 2002;105: 458-61.

8. Pramanik T, Shrestha S, Ghosh A. Apparently less value ofblood pressure among healthy people: Is the cuff widthresponsible? J Prev Med Hyg 2007; 48: 83-4.

9. S Ramdev. Pranayama Rahasya (Mystery of Breathingexercise). Divya Prakashana (publisher). Kripalu BagAashrama, Kankhal, Haridwar (city) 249408, Uttaranchal(state) India (country)

10. Pramanik T, Sharma HO, Mishra S, Prajapati R, Singh S.Immediate effect of slow pace Bhastrika pranayama on bloodpressure and heart rate. J Alter Complement Med 2009;15: 293-5.

11. Vialatte FB, Bakardjian H, Prasad R, Cichocki A. EEGparoxysmal gamma waves during Bhramari pranayama: ayoga breathing exercise. Concious Cogn 2009; 18: 977-88.

12. Jerath R, Edry JW, Barnes VA, Jerath V. Physiology of longpranayamic breathing: Neural, respiratory elements mayprovide a mechanism that explains how slow deep breathingshifts the autonomic nervous system. Med Hypotheses 2006;67: 566-71.

13. Matsumoto S, Ikeda M, Nishikawa T, Tanimoto T, YoshidaS, Saiki C. Inhibitory mechanism of slowly adaptingpulmonary stretch receptors after release from hyperinflationin anaesthetized rabbits. Life Sci 2000; 67: 1423-33.

14. Schelegle E, Green Schelegle J. An overview of the anatomyand physiology of slowly adapting pulmonary stretchreceptors. Respir Physiol 2001; 125: 17–31.

15. Siegelbaum R, Robinson S. Hyperpolarization activatedcation current: From molecules to physiological function.Annu Rev Physiol 2003; 65: 453-80.

16. Roberts L, Greene J. Hyper polarization–activated current:A characterization of subicular neurons in brain slices fromsocially and individually housed rats. Brain Res 2005;1040: 1-13.


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17. Cuttle MF, Rusznák Z, Wong AY et al. Modulation of apresynaptic hyperpolarization-activated current at anexcitatory synaptic terminal in the rat auditory brainstem. JPhysiol 2001; 534: 733-44.

18. Westbrook GL. In: Kandel ER, Schwartz JH, Jessell TM,eds. Principles of Neuroscience. New York: McGraw-Hill,2000.

19. Newberg A, Iversen J. The neural basis of the complex mentaltask of meditation: Neurotransmitter and neurochemicalconsiderations. Med Hypotheses 2003; 61: 282-91.

20. Lutz A, Greischar LL, Rawlings NB et al. Long-termmeditators self-induce high amplitude gamma synchronyduring mental practice. Proc Natl Acad Sci USA 2004; 101:16369-73.

21. Hainsworth R. Circulatory responses form lung inflation inanaesthetized dogs. Amer J Physiol 1974; 226: 247-55.

22. Daly M, De B, Robinson BH. An analysis of the reflexsystemic vasodilator response elicited by lung inflation indog. J Physiol London 1968; 195: 387-406.

23. Keel CA, Neil E, Joels N. Blood groups In: Samson Wright’sapplied physiology, 13th ed. Oxford UK; Oxford UniversityPress 1996; 46.

24. Ganong WF. Review of MedicalPhysiology. 22nd ed. Boston,Mc Graw Hill 2005; 605.

25. Lehrer PM, Vaschillo E, Vaschillo B. Heart rate variabilitybiofeedback increases baroreflex gain and peak expiratoryflow. Psychosom Med 2003; 65: 796-805.

26. Bernardi L, Porta C, Spicuzza L. Slow breathing increasesarterial baroreflex sensitivity in patients with chronic heartfailure. Circulation 2002; 105: 143-5.

27. Busek P, Kemlink D. The influence of the respiratory cycleon the EEG. Physiol Res 2005; 54: 327-33.

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Serum lipid and lipoprotein profile abnormality in predictingthe risk of coronary artery disease in non-diabetic patients

attending NMCTH, BirgunjM Adak and JN Shivapuri

Department of Biochemistry, National Medical College and Teaching Hospital, Birgunj, Nepal

Corresponding author: Dr. Manoranjan Adak, Associate Professor of Biochemistry, Department of Biochemistry,National Medical College and Teaching Hospital, Birgunj, Nepal; e-mail: [email protected], [email protected]

ABSTRACT

Dyslipidemia is one of the primary causes for coronary artery disease (CAD). Elevated total cholesterol (TC),triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C) and lowered high-density lipoprotein-cholesterol (HDL-C) are conventional risk factor in myocardial infarction patients. The present study wasundertaken with an objective to frame out the lipid and lipoprotein profile in non-diabetic patients attendingOPD of NMCTH, Birgunj. Out of 599 total patients, 317 patients were male and 282 patients were female. Themean±SD (mg/dl) levels of lipid, lipoprotein and their ratio among different age group were found increasedwith increasing age and these were statistically significant when compared with healthy control group. DesirableTC level (<200 mg/dl) in 73.0%, normal TG level (<150 mg/dl) in 59.0%, optimal level of HDL-C (<40 mg/dl)in 82.0% and normal LDL-C (<129 mg/dl) in 32.0% were found of the total population. Nearly 16% populationin total, male and female had normal (40-60 mg/dl) HDL-C respectively. Higher percentage of female (46.8%)than male (34.9%) had optimal level of LDL-C (<100 mg/dl). About 20.0% male had very high level of LDL-C (>160 mg/dl) while it was noted in 6.7% of female patients. Higher ratio of TC/HDL-C in both male andfemale patients was observed compared to controls and it was highest among >70 years age group. Higher ratioof LDL-C/HDL-C of all age group in male patients was observed when compared with control and it wasstatistically significant while in female patients the ratio was found increased significantly (p<0.05) after theage of 50 years. The study concludes that the importance of assessing the lipid profile and their ratio even in anormal individual as these are atherogenic factors for development of myocardial infarction and other coronarycomplications. The practice of computing the ratio should be practiced even in a normal health check uppackages.Keywords: Lipid profile, coronary artery disease, dyslipidemia, non-diabetes.

INTRODUCTION

Adverse lipid and lipoprotein profile have beenrecognized as independent risk factor for atherosclerosisand coronary artery disease (CAD).1,2 Lipid disorder isoften leads to myocardial infarction and heart failure.3

The relationship between cholesterol and saturated fatwith CAD is identified as early as in 1950s.4 It has beenshown that control of total serum cholesterol levels canreduce the incidence and mortality from coronary arterydisease.5,6 At present, it is firmly believed thatdyslipidemia is both atherogenic and thrombogenic.During dyslipidemia, a major biochemical change in thearteries took place due to accumulation of lipids eitherin the form of free cholesterol or its ester, which leadsto formation of plaques in inner wall of artery. If totalcholesterol level is below 150 mg/dl, no new plaqueswill be formed.7 Acute coronary event is expected whenthe plaques with thin fibrous cap ruptures. It is not thedegree of narrowing of the coronary artery but the natureof the plaque determines the onset of acute coronary

event. Dyslipidemia is known to increase plateletsaggregation, fibrinogen levels and platelets activationinhibitor.8 In addition, an elevated total cholesterol (TC),triglycerides (TG), low-density lipoprotein-cholesterol(LDL-C) and lowered high-density lipoprotein-cholesterol (HDL-C) are conventional risk factor formyocardial infarction as well as the major cause ofatherosclerosis.9-12 Low-density lipoprotein cholesterol(LDL-C) is the main therapeutic target in the preventionof CAD. The TG/HDL-C ratio is also widely used toassess the lipid atherogenesis.13 However, the utility ofthis ratio for predicting CAD risk is not clear.

CAD is associated with several factors, including raisedserum lipid and lipoproteins, an increase in LDLoxidation (free radical damage), increased plateletaggregation (clumping), increased plasma fibrinogen,coagulation factors, hypertension, alterations in glucosemetabolism, smoking, genetic and environmentalfactors.14,15 High intakes of fruits and vegetables are also


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associated with decreases in CAD risk markers includingtotal and LDL cholesterol,16 blood pressure.17 About70.0% of CAD can be prevented or delayed with dietarychoices and lifestyle modifications 18.Exercise and a dietwith minimal saturated lipid will help the patients toincrease their serum HDL and lower triglyceridelevels.19,20 Borderline hyprtriglyceridemia is usually dueto obesity, excessive alcohol intake, poorly controlleddiabetes mellitus, chronic renal failure, nephroticsyndrome or use of drugs like beta-blockers, estrogensand corticosteroids.21 Lipoprotein (Lp-a) has also beenidentified as an independent risk factor for thedevelopment of coronary heart disease.22

Global Burden of Disease Study reported that in 1990there were 5.2 million deaths from CAD in economicallydeveloped countries and 9.1 million deaths from thesame causes in the developing countries 23. It has beenpredicted that by the year 2020 there will be an increaseby almost 75.0% in the global CAD burden.24 Centersfor Disease Control and Prevention reported in 2006 thatmore than 910,000 people in the US die of CAD eachyear.25 Incidence of dyslipidemia is spectacularlyincreased day by day throughout the globe. A steadyincrease of cholesterol levels was noticed in Asiancontinent in the last decades of the 20th century and trendwas increasing faster in urban areas than in rural

areas.26,27 The prevalence of dyslipidemia with advancingage and obesity is also reported in worldwide.28,29 A groupof researchers conducted a series of hospital/clinicalbased study on lipid profile in Nepalese population inurban and rural areas of Nepal.30-35 Keeping in view allthese facts, this study has been conducted to evaluatethe prevalence of various lipids, lipoprotein profile andtheir ratios to HDL-C in non-diabetic adult patientsattending the OPD of National Medical College andTeaching Hospital (NMCTH), Birgunj.


This was a retrospective study conducted at NationalMedical College and Teaching Hospital (NMCTH),Birgunj, Nepal. All clinically suspected patientsattending at our outpatient department (OPD) withcommon symptomatic disease like fever, diarrhea, skindisease etc. were selected for study. Patients withdiabetes mellitus, hepatic impairment, bleeding disorder,renal problem were excluded from the study. Accordingto American Diabetes Association (ADA),36 thosepatients had impaired fasting glucose level 100-126 mg/dl, they were also excluded from the study. Detailedpresent and past histories of the patients were collectedfrom preset proforma. The proforma included name, age,sex, dietary habit, dirking habit, smoking habit, familyhistory of disease, socio-economic status, communityand occupation. Thus, a total 599 adult patients in theOPD were included in the study. Out of total patients,317 patients were male and 282 patients were female.Age of patients was considered from 21 years and morethan 70 years. They were categorized into six groupswith age of ten years interval. Total 190 (105 male and85 female) with sex and age matched from 21-50 years,healthy, non-diabetes and no other clinical complicationwere taken as control.

About 5 ml of venous blood was collected under asepticcondition from each individual. The blood was allowed

Agegroup Meanage Mean Lipid levels ±SD(mg/dl),n=317 TC/HDL-C TG/HDL-C LDL/HDL-C

TC TG HDL-C LDL-C

21-30 27.04±2.30 169.63±49.97 143.76±76.99# 32.52±4.39** 117.26±43.38 5.07±1.46# 4.19±1.67# 3.18±1.21#

31-40 35.30±2.84 178.43±54.45 165.60±87.15** 33.35±9.89** 102.18±39.19 5.08±1.47# 4.22±1.73# 3.21±1.33#

41-50 45.34±2.63 186.18±43.58# 151.23±90.68# 35.06±8.45 115.89±35.19 5.59±1.93** 4.39±1.97# 3.50±1.41**

51-60 54.65±2.87 189.36±56.01# 181.80±88.16** 34.26±8.43 128.86±43.11* 5.80±1.69* 4.80±1.69* 3.71±1.44**

61-70 64.96±3.08 204.37±43.83* 184.84±80.46* 34.20±8.17 134.05±45.68* 5.82±1.80* 4.89±1.57* 3.90±1.36*

>70 73.35±2.24 225.63±56.43* 190.43±79.19* 34.46±6.29 145.96±50.91* 5.87±1.64* 5.48±1.47* 4.51±3.58*

Control n=105 42.72±9.63 177.96±10.65 122.70±19.71 36.75±6.72 111.92±13.78 4.29±0.85 3.08±1.06 2.59±0.78

Table-2: Lipid levels and their ratio among different age groups in total male patients

TC=total cholesterol, TG=triglyceride, HDL-C= high-density lipoprotein-cholesterol, LDL-C= low

-density lipoprotein-cholesterol. Probability values (calculated as compared to control group using Student’s t-test) *<0.001, **<0.01 and #<0.05

Age group(years) Male Female Total %21 - 30 49 54 103 17.231 - 40 60 105 165 27.541 –50 58 53 111 18.551 60 89 38 127 21.261 - 70 33 22 55 9.2>70 28 10 38 6.3Total 317 (52.9%) 282 (47.1%) 599 100%

Table-1: Age and sex distribution of the patients (n=599)

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cut off value of p<0.05 was considered for the statisticalsignificance.

RESULTS

It was hospital based cases control study of lipid profileof non-diabetic adult population who were enrolled inthe OPD in National Medical College, Birgunj. It hasbeen found that out of total 599 patients, 317(52.9%)patients were male and 282 (47.1%) were female.Maximum female patients (105) and total number ofpatients (165, 27.55%) were found in the age group of31-40 years (Table-1).

Mean age, lipid levels and their ratios to HDL-C of thetotal male patents were represented in Table-2. Themean±SD (mg/dl) level of TC was found increased withincreasing age. After the age of 50 years, the level ofTC and TG difference were statistically significant(p<0.001) when compared with healthy control group.A decreased level of HDL-C was found from age group31-40 years and onwards. However, the LDL-C levelsof 21-30 years and 31-40 years were remained almostclose to control group but the levels rest of the age groupwere found increased with increasing age. On closer lookit has been found that LDL-C level was highest among>70 years age group and it was statistically significant(p<0.05).

Table-3 shows the mean±SD (mg/dl) levels of lipids,lipoproteins and their ratio among different age groupof total female patients. TC and TG both were foundincreased with increasing age and these were statisticallysignificant when compared with healthy control group.HDL-C level of first group (21-30 years) was foundslight higher than control group but inconsistentdecreased trend was found after age of 31 years. Noabnormality of LDL-C level was found in the femalepatients up to age of 40 years. However, a significantincreased level of LDL-C was found after 40 years ofage (p<0.05). It also has been found that more than 70

TC=total cholesterol, TG=triglyceride, HDL-C= high-density lipoprotein-cholesterol, LDL-C= low- density lipoprotein-cholesterol.Probability values (calculated as compared to control group using Student’s t-test) *<0.001, **<0.01 and #<0.05.


Agegroup Meanage Mean Lipid levels ±SD(mg/dl),n=282 TC/HDL-C TG/HDL-C LDL/HDL-C

TC TG HDL-C LDL-C

21-30 25.04±2.33 157.04±33.03# 114.10±35.56 38.07±11.50 93.33±27.29 4.36±1.26** 4.14±1.68# 3.18±1.38

31-40 34.42±2.53 160.43±54.97# 133.59±64.57# 33.87±4.61** 93.01±29.19 4.48±1.18# 4.18±1.78# 3.19±1.37

41-50 44.57±2.56 170.29±53.09** 133.89±63.54# 35.63±9.85# 102.44±39.46# 4.78±1.18** 3.79±1.70 3.22±1.35

51-60 52.95±2.28 182.03±36.46* 141.52±47.29** 34.06±5.85** 118.12±50.16# 5.35±1.98* 3.98±1.68 3.73±1.37#

61-70 63.77±2.966 183.14±56.55* 143.24±87.00* 33.10±4.61** 123.71±50.60# 5.78±1.65* 3.93±1.36 3.85±1.54#

>70 72.70±1.49 184.79±43.14* 143.25±79.19* 34.55±8.28# 126.46±49.46# 5.78±1.34* 4.25±1.89** 3.78±1.56#

Controln=85 36.18±7.57 134.58±13.51 119.74±16.54 37.26±5.81 93.00±23.74 3.41±0.62 3.55±0.62 3.22±1.69

Table-3: Lipid levels and their ratio among different age groups in total female patients

to clot at room temperature. The clot was rimmed,centrifuged and serum was stored in a sterile vial. Lipidprofile TC, TG, and HDL-cholesterol were analyzedenzymatically using kits obtained from RanbaxyLaboratories Limited, Mumbai, India and reading wastaken on semiautomatic analyzer (Microlab-300, VitaScientific, India). LDL-cholesterol level was calculatedby applying Freidelwald’s formula.37

Lipid levels were classified according to theclassification recommended by National CholesterolEducation Program (NCEP) and Adult Treatment panelIII (ATP III) guidelines.38 It provides evidence-basedrecommendations on management of high bloodcholesterol, relates disorders, and given the values forlipid levels in graded wise like total cholesterol asdesirable, borderline high, and high. Desirable level ofTC was <200 mg/dl, borderline was between 200-239mg/dl and high TC was considered when level was >240mg/dl. Level of TG was considered normal when it was<150 mg/dl, borderline was between 150-199 mg/dl,200-499 mg/dl was considered high TG and very highTG level was defined when it was >500 mg/dl.39

Desirable HDL-C was considered when it was >40 mg/dl. The LDL cholesterol level has been graded as optimal(<100mg/dl), normal (100-129mg/dl), borderline (190-159 mg/dl) and high (>160 mg/dl). Normolipidaemicsubjects were judged by the following criteria: LDL-C<130 mg/dl, HDL-C >35 mg/dl, TC <200 mg/dl; andTG <150 mg/dl.40

The ratio of TC/HDL-C, TG/HDL-C and LDL-C/HDL-C were analyzed and tabulated. Percentage distributionof the total study population according to aforementionedlipid profile was calculated. Percentage distribution ofmale and female was also separately calculated andtabulated.

The statistical analysis was carried out using the softwareprogram SPSS-10. Statistical significance was calculatesas compared to control group using Student’s t-test. The

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years age group of female patients have highest level ofLDL-C and it was statistically significant as comparedto healthy control group (p<0.01).

The ratio of TC/HDL-C, TG/HDL-C and LDL-C/HDL-C for male and female patients was shown in Table-2and Table-3. Higher ratio of TC/HDL-C in both maleand female patients was observed compared to controls.TG/HDL-C ratio of male patients was found increasedwith increasing age and it was highest among >70 yearsage group. However , in female patients the ratio of TG/HDL was found increased significantly in 21-30 years,31-40 years (p<0.05) and >70 years age group (p<0.01)respectively. Higher ratio of LDL-C/HDL-C of all agegroup in male patients was observed when comparedwith control and it was statistically significant. The ratioof LDL-C/HDL-C of female patients in 21-30 years, 31-40 years and 41-50 years age group was found in almostnear to control group and the ratio was found increasedsignificantly (p<0.05) in the rest of age group.

The desirable level of TC was found 66.5% in male,80.45% in female and 73.1% in the total populationrespectively; however about 11.0% of the total populationhad high (>240 mg/dl) TC level (Table-4). Higher levelof TC was observed among males (14.81%) than infemales (6.0%). Similarly, normal TG level was found in59.1% of total population. Normal level of TC and TGwas found in almost 81.0% in females as compared tomales. It was also found that about 26.0% males had high(200-499 mg/dl) TG level when compared with femaleas well as total population (Table-4).

An optimal level of HDL-C (>40 mg/dl) was found inalmost 82.0% in individual population and totalpopulation. Nearly 16.0% population in total, male andfemale had normal (40-60 mg/dl) HDL-C respectively.Higher percentage of female (46.8%) than male (34.97%) had optimal level of LDL-C (<100 mg/dl). About

20.0% male had very high level of LDL-C (>160 mg/dl)while it was noted in 6.7% of female patients (Table-5).

DISCUSSION

Dyslipidemia is one of the major risk factor of coronaryartery disease (CAD). Incidence of dyslipidemia is atpresent a global burden,23 which can be modified eitherby proper dietary choices or by lifestyle modifications19

or medical management. Therefore, the present hospital-based (NMCTH) clinical study was designed to evaluatelipids, lipoprotein profile and their ratios to HDL-C innon-diabetic patients. Present study showed the meanTC and TG levels were increased with increasing age inboth gender. This finding correlates well with one studythat has been conducted in male population insoutheastern Nepal.41 Decreased levels of HDL-C werefound from age group 31-40 years and onwards in bothgender. The LDL-C level was found highest among >70years age group in male as well as female patients. Agroup of Nepalese researcher has also been reported thesame result about LDL-C level.31 However, lipid levelin this survey is slight higher in comparison with onereport from eastern part of Nepal.42 A higher value forTC has been reported in acute myocardial infarctionpatients than the subjects without infarction.43,44 Otherinvestigators has been reported also the higher TG(>150mg/dl) among adult male population living in hillyregion of eastern Nepal and has thought to be due intakeof carbohydrates and polyunsaturated fatty acids (PUFA)which normally inhibit the synthesis of TG in situ in theliver.32,41 Increase level of cholesterol can be due tochanging of lifestyle of the people associated with rapidurbanization as well as globalization. The increase levelof cholesterol has also been reported in other Asiancountries during the last decade of the 20th

century27.Chinese worker has also been reported asignificant increase in hypercholesterolemia,

Sex HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl)Optimal <40 Normal 40 - 60 High >60 Optimal <100 Normal100-129 Borderline 130-159 High 160

Male 260(81.9%) 51(16.1%) 6(1.9%) 111(34.9%) 97(30.6%) 45 (14.2%) 64(20.2%)Female 232(82.3%) 45(15.9%) 5(1.8%) 132(46.8%) 96(34.0%) 33(11.7%) 19(6.7%)Total 492(82.1%) 96(16.0%) 11(1.8%) 243(40.6%) 193(32.2%) 78(13.0%) 83(13.9%)

Table-5: Percentage distribution of HDL-C and LDL-C in male and female patients.

<_

Table-4: Percentage distribution of total serum cholesterol and triglyceride levels in male and female patients

Sex Total cholesterol level(mg/dl) Total triglyceride level(mg/dl)Normal <200 Borderline200-239 High 240 Normal <150 Borderline150-199 High200-499 Very high 500

Male 211(66.5%) 59 (18.6%) 47(14.8%) 154(48.5%) 76 (23.9%) 82(25.8%) 5(1.6%)Female 227(80.4%) 38 (13.5%) 17(6.0%) 200(70.9%) 59 (20.9%) 22(7.8%) 1(0.3%)Total 438(73.1%) 97 (16.2%) 64(10.6%) 354(59.1%) 135 (22.5%) 104(17.4%) 6(1.00%)

<_<_

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hyprtriglyceridemia and abnormally low HDL-C in allage group of professional population.28,45 A serialepidemiological survey in Indian population has alsodemonstrated an abnormal change of lipid profile in bothmale and female.46-48 Framingham study hasdemonstrated the correlation between low HDL-C andCAD as an independent risk factor.49 Unhealthy life stylechange and use of lipid lowering drug are the mainpossible causes of adverse lipid profile in the regions.50

Present study showed the desirable TC level in 73.0% ,normal TG level in 59.0% , optimal level of HDL-C(<40mg/dl) in 82% and normal LDL-C (<129 mg/dl) in32.0% of the total population. The results of presentsurvey on the prevalence of dyslipidemia werecomparable with the study of Iraqis population.51 Highlevels of TC, TG and LDL-C were observed respectivelyabout 11.0%, 17.0% and 14.0% o the total population.Most interesting point noted in the male population hadsignificant high level of lipid profile and lipoprotein LDLin comparison to female population. This correlates wellwith high incidence of coronary artery disease in malepopulation.30,52 Diet, body weight and smoking habitsmay be possible cause of increased magnitude of LDL-C in male population.53 Various epidemiological datahave shown a linear correlation with LDL-C and CAD.54

The TC/HDL-C ratio in non-diabetic male and femalepatients was significantly higher compared with controls.Goswami et al had observed a similar TC/HDL-C ratioin normolipidaemic subjects of the age group 21-70years.43 Lower ratio of TC/HDL-C were observed inacute myocardial infarction patients in study conductedelsewhere.55 These data indicate though the TC levelswere within the normal level; the TC/HDL-C ratio waselevated significantly in non-diabetic patients indicatingthe importance of assessing TC/HDL-C ratio even innormolipidaemic subjects.

Increased TG and decreased HDL-C are also thought tobe atherogenic and thus increased ratio of TG/HDL-Cwould indicate an increased atherogenic risk. The presentstudy observed significantly higher ratio in OPD patientscompared with control. A slightly higher ratio (2.5) hasbeen reported in healthy subjects elsewhere 55 and somestudies have reported higher ratios,11,56,57 whereas NCEPATP-III a cut of level of 2.5 has been suggested.40

Increased LDL-C and reduced HDL-C are consideredhighly atherogenic. Thus, the increased level of LDL-C/HDL-C would indicate an increased risk of developingatherosclerosis. A cut of level of 1.6 has been suggested.40

The present study observed significantly higher ratio innon-diabetic OPD patients compared with control .Resultsreported on the ratio were inconsistent, as some studies

reported higher ratios43,58 and lower ratios59 of LDL-C/HDL-C compared to the present study.

Hence, it can be concluded that increase in all thefractions of lipid profile, as observed in non-diabeticOPD patients attending NMCTH can explain theincreased risk of CAD. It has also been concluded theimportance of assessing the lipid ratios even in a normalindividual as it is one of the atherogenic factors fordevelopment of myocardial infarction and other coronarycomplications. The practice of computing the ratioshould be practiced even in a normal health check uppackages.

ACKNOWLEDGEMENTSAuthors are thankful to Prof (Dr) AN Thakur, HOD, Dept. ofPathology and Central Laboratory for their support andcooperation. I am very much thankful to Board of Directorsand Principal of National Medical College for their invaluableinspiration and support. Finally, I express my sincere thankto all Technicians and staffs of Central laboratory of NMC,for their help without which this study could not have beenpossible.

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Changing tuberculosis trends in Nepal in the period 2001-2008L Shrestha,1 KK Jha2 and P Malla3

1Community Medicine, Technical Advisor, HIV/AIDS, Save the Children, Nepal, 2Director, SAARC TB and HIV/AIDS Centre,Bhaktapur, Nepal, 3Director, National Tuberculosis Center, Bhaktapur, Nepal

Corresponding author: Dr. Lochana Shrestha, Technical Advisor, HIV/AIDS, Save the Children, NepalGPO Box 9517, Kathmandu, Nepal ; e-mail: [email protected]

ABSTRACT

To assess the trends on indicators of TB control in Nepal over a period from 2001-2008. Retrospective analysisof information from Annual Reports of NTP, Nepal from 2001-2008. The incidence of New Smear Positive(NSP) TB declined from 58.9 in 2001 to 53.4 in 2006 per 100000 populations then reversed in the period 2006-2008. This TB incidence decreased in males and the age group <45 years (except 0-14 years). The notificationrate of all cases of TB declined by 3 % overall over the entire period from 2001 to 2008. Mortality amongsmear negative and extra pulmonary declined significantly. The failure rate and defaulter rate were declinedsignificantly and the case detection rate (CDR) was increased significantly within the study period. Increasingtrend in CDR, Treatment success rate and decreasing trend in failure rate, defaulter rate are the evidence ofprogress of NTP, in Nepal. Since there is reversal of incidence of NSP from 2006, a detailed analysis ofexisting TB control measures is required. If the success is continued and quality care is provided as perInternational Standard of TB Care, the Millennium Development Goals will be an achievable target.Keywords: Tuberculosis, trend, indicators of TB.

INTRODUCTION

Nepal is situated between India and China. It has anestimated population of above 26 million.1 Tuberculosis(TB) is still a potential threat to public health, and itrequires close epidemiological surveillance at nationaland international levels to ensure efficient control of thedisease. It still remains one of the major public healthproblems in Nepal. Health services for TB are providedby Government of Nepal’s Basic Health Services, Privatesectors and international or national non governmentalorganizations. While TB is a serious problem in low andmiddle income group in this country,2 Nepal is workingfor the control of the disease by launching National TBControl Programme in 1965 and adopted DOTS strategyin 1996. By the year 2001 DOTS based TB controlservices were provided in all the 75 districts of thecountry. Government of Nepal is committed to fightagainst TB and it has given the status of priority for thisprogramme. There is commitment from different donorsto support New Stop TB strategy, which has beenadopted by the programme in 2006 in order to providemore comprehensive TB control measures. TheProgramme has achieved both the global target oftuberculosis as 70.0% case detection and treatmentsuccess rate of 88.0%.3 Multi Drug Resistant TBmanagement programme has been launchedsubsequently in 2005, which is considered a globalmodel for ambulatory treatment. However, there areseveral critical challenges and issues which need to be

addressed to move towards the achievement ofMillennium Development Goals (MDG) goals.

Among the SAARC Member States (Afghanistan,Bangladesh, Bhutan, India, Maldives, Nepal, Pakistanand Sri Lanka), Nepal is not ranked as High BurdenCountry by WHO.4 However, according to TB controlprogramme of Nepal, about 50.0% population is infectedwith TB, of which 60.0% are adult. Every year, 21,827smear positive infectious TB incidence cases areexpected to rise in the country. Although introductionof DOTS has already reduced the numbers of deaths,however 5,000 to 7,000 people still continue to die eachyear.3

Now that tuberculosis control programmes are beingurged to assess progress towards the MDG,5 our aim isto provide some insight information in this regard byassessing the trends of TB indicators in Nepal from 2001to 2008 which might help to identify the factors thatneed to address to meet MDG within specific timeframe.

MATERIALS AND METHOD

National Tuberculosis Centre (NTC) is the single unitsituated in Bhaktapur district, which is dealingexclusively with TB Control Programme of Nepal.Annual reports of TB Control Programme have beenpublished since its inception. A retrospective analysiswas conducted on routine programme data in annualreports of the programme from 2000/2001 to 2007/08.


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Because this was a record based retrospective study,ethical approval was not required.

The National Tuberculosis Programme policy is toprovide with free diagnostic and treatment services toall TB patients registered in the programme. Allcompliance of treatment is directly observed by trainedand regularly supervised health workers or volunteers.The sputum smear microscopy remains the key tool fordiagnosis of infectious tuberculosis. There are currently427 microscopy centers offering smear microscopyservices, among these 354 operates within GovernmentHealth system, 49 through partner NGOs and 24 inprivate sector.3

The NTP maintains a regular reporting system on case

finding, sputum conversion, treatmentoutcomes from all levels of theprogramme by trimester. Data wascompiled and published in annualreport.

Indicators of TB control such asincidence of New Smear Positive(NSP), case finding of new smearpositive, and treatment outcomeswere assessed. In addition, patients,age and sex distribution among smearpositive cases and mortality trend fordifferent types of TB cases wereanalyzed after notification.

For the calculation of incidence rate,newly registered sputum smearpositive cases were included and for

mortality rate all tuberculosis deaths amongst registeredTB cases were included. Since national vital registrationsystem for death showing the cause of death is notproperly maintained in country, death recorded in TBregister is taken as source of mortality data for TB.Relapse cases do not include defaulters or failure cases.Population denominator data were obtained from Annualreports itself which presented on the basis of growthrate provided by Bureau of Statistic, Government ofNepal. Statistical package SPSS-12 version for windows95.7.5 was used for different analysis.

RESULTS

The incidence of smear positive tuberculosis was 58.9/100000 in 2001. The average annual rate of decline was 2.0%

Source: Annual report of NTP, Nepal (2001-2008)* per 100 000 population**IRi - IRq / IRq, where IRi = incidence rate in the last year and IRq =incidence rate of thereference year# ( IRi - IRq / IRq,)/n-1, where n=total number of years of the period

2001 2008 Variation trend TB incidence TB incidenceRegion n (%) Rate* n(%) Rate Overall** trend annual# meanEastern 6577(21.7) 122 6208(18.5) 103 -16 -2Central 11458(37.8) 142 13725(41.0) 151 6 1Western 5461(18.0) 119 5815(17.4) 109 -8 -1Midwestern 4538(14.9) 150 4871(14.5) 143 -5 -1Far western 2241(7.4) 101 2800(8.3) 112 11 2Total 30275(100) 123 33419(100) 127 3

Table-1: TB (all forms) incidence by region, Nepal, 2001 and 2008

Table-2: Age distribution of New Smear positive cases in Nepal (2001-2007)

Age- 0-14 15-24 25-34 35-44 45-54 55-64 65+Years

n (%) Rate* n (%) Rate* n (%) Rate* n (%) Rate* n (%) Rate* n (%) Rate* n (%) Rate*2001 326 (2.4) 1.4 3252(23.8) 14.0 2769(20.3) 11.9 2581(18.9) 11.1 2064(15.1) 8.9 1675(12.3) 7.2 997(7.3) 4.32002 331(2.4) 1.5 3183(23.2) 14.0 2748(20.0) 12.1 2482(18.1) 10.9 2123(15.5) 9.3 1891(13.8) 8.3 956(7.0) 4.22003 311(2.2) 1.3 3322(23.2) 13.9 2765(19.3) 11.5 2492(17.4) 10.4 2378(16.6) 9.9 2125(14.8) 8.9 955(6.7) 4.02004 309(2.1) 1.3 3273(22.4) 13.4 2887(19.8) 11.8 2501(17.1) 10.2 2387(16.3) 9.7 227915.6 9.3 978(6.7) 4.02005 343(2.3) 1.4 3154(21.5) 12.5 2796(19.1) 11.1 2519(17.2) 10.0 2464(16.8) 9.8 2294(15.7) 9.1 1088(7.4) 4.32006 304(2.2) 1.2 3078(21.9) 12.0 2652(18.9) 10.3 2428(17.3) 9.5 2302(16.4) 9.0 2214(15.8) 8.6 1051(7.5) 4.12007 325(2.3) 1.2 3174(22.1) 12.1 2618(18.2) 10.0 2429(16.9) 9.2 2339(16.3) 8.9 2293(16.0) 8.7 1177(8.2) 4.5Total 2249(2.3) 1.3 22436(22.6) 13.1 19235(19.4) 11.2 17432(17.5) 10.2 16057(16.2) 9.4 14771(14.9) 8.6 7202(7.2) 4.2

Age group 0-14 15-24 25-34 35-44 45-54 55-64 65+% Total** -14 -14 -16 -17 0 21 5 %annual mean** -2 -2 -3 -3 4 1

Z value 0.55 3.38 4.45 4.36 -2.76 -8.91 -2.81

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from 2001 to 2006, with a slight rise of 2.0% per year from2006 to 2008. In comparing the incidence of New Smearpositive TB with Gross Domestic Product (GDP)growth of Nepal6 till 2006, along with decline of GDPgrowth from 2001 to 2005, the incidence decrease,thereafter both increased (Fig 1 and 2).

The incidence rates of all forms of TB were reportedhighest in mid-western region and lowest in far westernregion in 2001, whereas in 2008 highest in central andlowest in eastern region of Nepal. A decline was reported

in eastern region (16.0% overall and 2.0% annually), inwestern region (8.0% overall and 1.0% annually) and inmid-western region (5.0% overall and 1.0% annually),where as in other regions the incidence was increasing,with a highest incline in far western region (11.0%overall and 2.0% annum) in the period from 2001 to2008 (Table-1).

The trend in notification rates of all cases and differenttypes of TB is demonstrated in Fig. 3. The notificationrate of all cases of TB declined from 130 in 2001 to 126per 100000 populations in 2008, the overall decline was3.0% over the entire period from 2001 to 2008. Similarly,the notification rate of smear negative cases declinedfrom 39 in 2001 to 35 per 10000 populations with inthis period. However notification rate of extra pulmonaryTB cases increased from 21 to 25 per 100000 populationswithin 7 years gap.

The incidence of NSP TB showed significant declinedin age groups before 45 except in 0-14 years, andsignificant increased after 54 age group over the periodfrom 2001 to 2007. The greatest decrease occurred inthe age group 35-44 years (17.0% overall and 3.0%annually), while in young age group 0-14 years therewas a decrease of 14.0% overall and 2.1% annually. Inevery year it showed that an incidence is peak among 15-24 age groups followed by 25-34 age groups (Table-2).

In males, the annual incidence of smear positivetuberculosis decreased from 39.3 in 2001 to 38.4/100000in 2008 at a rate of 2.0% overall. In females, the

Years New Smear Smear Negative Extra Pulmonary Relapse Failure Return afterPositive default (RAD)

No. Regd No Died No. Regd No Died No. Regd No Died No. Regd No Died No. Regd No Died No. Regd No Died2001 13579 636 8907 501 4848 202 1798 107 237 19 517 43

4.6 % 5.6% 4.2% 5.9% 8% 8.3%2002 13669 739 9496 494 5185 201 1898 124 300 22 465 37

5.4 % 5.2% 3.8% 6.5% 7.3% 7.9%2003 14288 784 8786 543 5555 232 2052 160 293 26 395 36

5.5 % 6.2% 4.2% 7.8% 8.9% 9.10%2004 14554 776 8903 504 6268 273 2065 121 426 28 361 32

5.3 % 5.6% 4.3% 5.8% 6.5% 6.4%2005 14625 755 9489 539 6999 253 2341 130 316 28 312 29

5.1% 5.7% 3.6% 5.5% 8.9% 9.3%2006 14028 653 9170 438 7089 275 2383 128 285 21 252 24

4.6 % 4.8% 3.9% 5.4% 7.4% 8.3%2007 14355 652 9350 374 6986 214 2249 109 230 16 269 21

5.0 % 4.0% 3.0% 4.8% 6.9% 7.8%

Table-4: Mortality among tuberculosis patients registered in NTP, Nepal

Z value 0.78(P=0.21) 6.24 (P=<0.05) 1.70 (P=0.04) 1.54 (P=0.06) 1.31 (P=0.09) 0.58 (P=0.28)

L Shrestha et al

Decline Male Female% total -2 -11% Annual Mean -0 -2

Male FemaleYear n. (%) Rate/lakh n. (%) Rate/lakh2001 9130 (66.8) 39.3 4534(33.2) 19.52002 9304(67.8) 40.9 4410(32.2) 19.42003 9581(66.8) 39.9 4767(33.2) 19.92004 9725(66.5) 39.7 4889(33.5) 19.92005 9886(67.4) 39.1 4772(32.6) 18.92006 9522(67.8) 37.1 4507(32.1) 17.62007 9756(67.9) 37.1 4599(32.0) 17.52008 10088(68.9) 38.4 4552(31.1) 17.3Total 77292 39.1 37030 18.7

Table-3: Sex Distribution of New Smear positive cases(2001-2008)

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corresponding values were19.5 and 17.3 with an annualdecrease of 2.0% (Table-3).

The mortality trend among different types of TB showedincreasing trend till 2003, then start decreasing till 2007.Among smear negative tuberculosis there was significantdecline (Z=6.24, p<0.05), and also among extrapulmonary (Z=1.70, p=0.04), where asamong new smear positive the decline wasnot significant (Table-4).

On the analysis of data on adversetreatment outcomes of New smear positivetuberculosis, it showed that the failure rateand defaulter rate decreased significantlyin the period from 2000 to 2007, whiletransfer out rate increased insignificantlyin this period (Fig. 4).

Treatment success rate ranged between87% in 2000 and 88% in 2007. Casedetection rate ranged between 67.0% in2000 and 72.0% in 2008. Regarding case

detection rate there was significant rise overthe period from 2000 to 2008 (Z=10.48, p <0.05) (Fig. 5).

DISCUSSION

Nepal is a country faced with manychallenges including poverty, illiteracy andpolitical instability. Despite these problemsNTP, Nepal has made considerable successover the past years. This is due to strongpolitical commitment of the government ofNepal and the priority given to TB control.Similarly, the TB project study inBangladesh7 showed considerable successdue to strong political commitment of thegovernment of Bangladesh.

The current trend of tuberculosis in Nepal ispromising based on a detection rate in 2008of 72.0% and treatment success rate of 88.0%with some challenges to TB control.

The incidence of New Smear Positive (NSP)tuberculosis in Nepal showed a steadydecline till 2006 and thereafter increases andreached to 55.7 per 100000 populations in2008, where as in neighboring countries likeIndia8 showed slow inclination and inPakistan9 there is steady inclination since2001. Study regarding epidemiology of TBin Kuwait showed a steady decline from 1965to 1989 and thereafter slight increase in theincidence till 1999.10 The slower decline

before 2006 and slow incline after 2006 in this studycan be explained by multi-drug resistant and TB/HIVco-infection which are directly related to the resurgenceof TB elsewhere in the world.11

The overall incidence of all forms of TB, declined in allregions except in central and far western region, which

Fig. 3. Trend of notification of all and different types of TB cases,2001-2008

Fig. 1. Trend of incidence of new smear positive TB cases, 2001-2008

Decline; %total= -9 % and %Annual Mean = -2% till 2006, thereafter,total=4% and % Annual Mean = 2%

Fig. 2. Trend of real GDP growth, Nepal, 2001-2006

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might be due to increase accessibility and availabilityof health services in these areas. During the last 8 years,slower decline in TB of all forms and smear negativenotifications have been observed, whereas notificationsof extra pulmonary cases have been increased. Similarsituation in relation to extra pulmonary cases observedin neighbor countries like India,8 Pakistan9 andBangladesh.12

Though the incidence of NSP is highest among 15-24years group in every year, the rate of occurrence of NSPin this age group is significantly decreasing withpreceding years, while the occurrence of same isincreasing among elderly group. If this occurrence iscontinued to be increased among elderly, it could beassured that there will be age shifting in relation to TBoccurrence in future. While tuberculosis trend study inSouth India13 showed a decreasing trend in age groupless than 35 years. Similar study in Cuba14 showed thatthere is decrease in incidence of NSP in all age groupfrom 0-64 years. Males had consistently higher incidencethan females with an average ratio of 2.05 for smearpositive tuberculosis in this study; where as study in

South India12 showed 4.5 average ratiofor this group of tuberculosis.

Trend of mortality showed thesignificant decline among smearnegative and extra pulmonary which isdifferent from mortality trend study inDelhi,15 which showed a significantdecline among new smear positivecases. Based on this information, wecould state that NTP, Nepal needs tolook into the factors that might help tobring about significant decline inmortality among NSP.

In analysis of adverse treatmentoutcomes among NSP, there issignificant decline in failure rate anddefaulter rate, similar findings inrelation to default rate found in studyin Delhi.15 This shows that treatmentadherence is improving under the TBControl programme of Nepal.

Information in epidemiological trend intuberculosis is of great importance forplanning, monitoring and evaluatingNTP. Increasing trend in case detectionrate, treatment success rate anddecreasing trend in failure rate,defaulter rate are the evidence ofprogress of TB control programme inNepal. If the success is continued and

quality care is provided as per International standard ofTB care of Stop TB Strategy, Millennium DevelopmentGoals will be an achievable target.

Since there is reversal of incidence of NSP from 2006, adetailed analysis of existing TB control measures isrequired. In conclusion though the TB controlprogramme is successful, further progress is thereforenecessary mitigating the problems for the TB control.In addition, NTP Nepal needs to tackle the increasingproblems on HIV, MDR-TB, which may probablyincrease TB incidence in future, with scaling up theresponses focusing the components of Stop TB strategyand cross border issues related to TB control as Nepalhas open border with High Burden Country like India.

ACKNOWLEDGMENTSThe authors would like to thank all those working in NationalTuberculosis Control Programme of Nepal.

REFERENCES

1. Central Bureau of Statistics, Kathmandu, Nepal. Statisticalpocket book 2006.

2. World Health Organization. WHO report 2004. Global

Fig. 4. Trend of adverse treatment outcomes among new smear positive TBcases, 2000-2007

Z=2.11, P=0.01, Significant decrease in Failure rateZ=9.18, P=<0.05. Significant decrease in Default rateZ=-5.52, P=>0.05. Insignificant increase in transfer out rate

Fig. 5. Trend of treatment success and case detection rate (CDR),2000-2008

Z value for CDR= 10.48, P=<0.05

L Shrestha et al

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tuberculosis control-surveillance, planning, financing. WHO/HTM/TB/2004.331. Geneva, Switzerland:WHO, 2004.

3. Ministry of Health, Department of Health Services, NationalTuberculosis Centre. Annual report of tuberculosis controlprogramme, 2007/2008, Nepal.

4. World Health Organization. Global tuberculosis control-epidemiology, strategy, financing. WHO/HTM/TB/2009. 411.Geneva: WHO, 2009.

5. Bassili CD , Bierrenbach AL, Brockmans JF et al. Measuringtuberculosis burden, trends and the impact of controlprogrammes. Lancet 2008; 8: 233-43.

6. SAARC Human Resource development Centre, Islamabad,Pakistan. Database Profile on Macroeconomic and HRDindicators in the SAARC Region (1990-2006): 29.

7. Kumaresan JA, Md. Ahsan Ali A K, Parkkali L M.Tuberculosis Control in Bangladesh: Success of the DOTSStrategy. Int’l J Tuberc Lung Dis 1998; 2: 992-8.

8. Ministry of Health and Family welfare, Directorate Generalof Health Services, Central TB Division. RNTCP status report2001-2008, India.

9. Ministry of Health, Government of Pakistan, National TBControl Programme. Annual Report 2001-2007, Pakistan.

10. Behbehani N, Abal A, Al-Shami A, Enarson A. Epidemiologyof tuberculosis in Kuwait from 1995-1999. Int’l J Tuberc LungDis 2002; 6: 465-9.

11. Porter JD, McAdam KP. The re-emergence of tuberculosis.Annu Rev Public Health 1994; 15: 303-23.

12. Ministry of Health and Family welfare, Directorate Generalof Health Services, National Tuberculosis ControlProgramme. Tuberculosis control in Bangladesh, AnnualReport 2001-2008.

13. Radhakrishna S. Trends in the prevalence and incidence oftuberculosis in South India. Int’l J Tuberc Lung Dis 2001;5: 142-57.

14. Gonzalez E, Armas L, Lianes MJ. Progress towardstuberculosis elimination in Cuba. Int J Tuberc Lung Dis. 2007;11: 405-11.

15. Dhingra VK, Agarwal N, Chandra S, Vashist RP. TuberculosisMortality Trends in Delhi after Implementation of RNTCP.Indian J Tuberc 2009; 56: 77-81.


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A study of depression and anxiety in cancer patientsP Thapa, N Rawal and Bista Y

Department of Neuropsychiatry, Shree Birendra Hospital, Kathmandu, Nepal

Corresponding author: Dr. Prashwas Thapa, MBBS MD, Consultant Neuropsychiatrist, Department of Neuropsychiatry,Shree Birendra Hospital, Kathmandu, Nepal; e-mail: [email protected]

ABSTRACT

The aim of the study was to assess the prevalence of depression and anxiety in cancer patients. A cross sectionalcase control study design was used. Severely or terminally ill cancer patients and patients suffering from otherconcomitant illnesses were excluded from the study. Depression and anxiety was assessed on 50 cancer patients(cases) and on 50 healthy individuals (controls). The tools used were Structured Proforma (for recording socio-demographic details and relevant medical history), General Health Questionnaire (GHQ) and Hospital Anxietyand Depression Scale (HADS). A total of 30 (60.0%) were detected as ‘cases’ or having psychiatric morbiditybased on a cutoff score of above 2 on 12 item GHQ. Depression was present in 28.0% of cancer patientswhereas 40.0% of cancer patients had anxiety as per HADS.Keywords: Depression, Anxiety, Cancer, GHQ, HADS.

INTRODUCTION

The word cancer still conjures up deep fears of a silentkiller that creeps upon us without warning. Cancerevokes such desperation that it becomes a metaphor forgrief and pain, a scourge straining our intellectual andemotional resources.

Despite recent advances in securing remission andpossible cure, cancer still remains a disease equated withhopelessness, pain, fear and death. Its diagnosis andtreatment often produces psychological stresses resultingfrom the actual symptoms of the disease, as well aspatient’s and family’s perception of the disease. Patientshave common fears, which have been called six Ds:death, dependency on family, spouse and physician;disfigurement and change in early appearance and selfimage, sometimes resulting in loss or changes in sexualfunctioning; disability interfering with achievement ofage appropriate tasks in work, school or leisure roles;disruption of interpersonal relationships; and finally,discomfort or pain in later stages of illness.1

Cancer is associated with significant psychosocialmorbidity. Many researchers have reported that sixmental disorders occur more frequently in cancer patientsto warrant a detailed assessment and clinicalintervention. Three represent direct reaction to illness:adjustment disorders with depression and/or anxiety,major depression and delirium. Others (primarily anxietydisorders, personality disorders and major depressivedisorders) are pre existing conditions often exacerbatedby the illness.2,3

In the new millennium, a significant base of literature,training programmes, and a broad research agenda has

evolved with applications at all points on the cancercontinuum: behavioral research in changing lifestylesand habits to reduce cancer risk, study of behaviors andattitudes to ensure early detection; study of psychologicalissues related to cancer risks and testing; symptomcontrol (anxiety, depression, delirium, pain, and fatigue)during active treatment; management of psychologicalsequelae in cancer survivor; and management of thepsychological aspects of palliative and end of life care.Links between psychological and physiological domainsof relevance to cancer risk and survival are being activelyexplored through psychoneuroimmunology. Research inthese areas will occupy the research agenda for the firstquarter of the new century. At the start of the thirdmillennium, psycho oncology has come of age as oneof the youngest subspecialties of oncology, as one ofthe most clearly defined subspecialties of consultationliaison psychiatry.4-6

Depression in cancer patients may results from (a)situational stress related to the cancer diagnosis andtreatment (b) medications (steroids, interferon, or otherchemotherapeutic agents) (c) a biologically determineddepression ( endogenous or major depression), which isnot related to a precipitating event, or (d) recurrence ofa bipolar mood disorder. The first two are the mostcommon.1 Though the exact etiology of depression incancer is unknown, but several factors have beensuggested including the emotional impact of a cancerdiagnosis, side effects of treatment, progression of cancerwith associated disability, and symptoms and cerebraldysfunction associated with carcinomatosis;7 disruptionof key relationship, dependence, disability, disfigurementand approaching death.8


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Additional risk factors specific for the development ofdepression in cancer patients include certain primarytumor sites, advanced disease state with decliningphysical status, and certain anticancer treatment methodsincluding particular surgical procedures,chemotherapeutic regimens, and radiotherapy.9-13

Anxiety occurs in many patients with cancer varyingfrom the “normal” worries and fears associated with alife threatening illness, through subsyndromal distress,adjustment disorders, and generalized anxiety disordersand anxiety due to the medical condition.14,15 The fourcommon cause of anxiety in patients with cancer are asfollows: (a) Situational: which includes diagnosis orillness relate crisis, conflict with family or staffs,anticipating a frightening procedure or test results, andfear of recurrence (b) Disease related: poorly controlledpain, abnormal metabolic states, hormone secretingtumors, paraneoplastic syndromes (remote centralnervous system effects) (c) Treatment related: such asanxiety producing drugs (antiemetic, neuroleptic,bronchodilators), withdrawal states (opioids,benzodiazepines, and alcohol), conditioned(anticipatory) anxiety, nausea, and vomiting with cyclicchemotherapy and (d) Exacerbation of preexistinganxiety disorder: Phobias (needles, claustrophobia),Panic and generalized anxiety disorders, Post traumaticstress disorders or as a result of traumatic cancertreatments (eg. Bone marrow transplant).16 Most frequentis situational anxiety associated with hearing thediagnosis, or reaching a crisis in illness or treatment,during conflicts with staffs of family, anticipating afrightening procedure or a test result, and fear ofrecurrence. Disease related anxiety occurs most oftenwith poorly controlled pain.


The aim of the study was to assess psychiatric morbidityin cancer patients.

The objectives of the study were to: 1.) To study theprevalence of depression in cancer patients, 2.) To studythe prevalence of anxiety in cancer patients

Materials used in the study: A structured proforma wasused for recording socio-demographic profile andrelevant medical history. All the 50 cancer patients and50 controls (healthy individuals) were administered the

following psychological tests.

A. General Health Questionnaire(GHQ): GHQ is a screening instrumentdeveloped to assess the extent of non-psychotic psychiatric illness and currentmental well being for the past few

weeks.17 It is extensively used in both communitysettings and general practice. This scale has beenextensively validated over cultures, languages, agegroups (except extremes of ages), gender and educationwith very high sensitivity and specificity. GHQ 12 wasused in present study. Scoring was done by using binarymethod with 2 as cut off score.

B. Hospital Anxiety and Depression Scale (HADS):The HADS is a self-report questionnaire developed todetect adverse anxiety and depressive states.18 Since itwas developed for use in non-psychiatric departments,it does not rely upon symptoms that may be present inpeople with physical illness alone, such as pain andweight loss. Subjects are asked to choose one responsefrom the four given. They should give an immediateresponse and be dissuaded from thinking too long abouttheir answers. The Questions relating to anxiety aremarked ‘A’ and to depression ‘D’. It has 14 items, 7related to anxiety and 7 to depression. Scoring is from0-3 and score ranges from 0-56. The norms give an ideaof the level of anxiety and depression (0-7=normal, 8-10=mild, 11-14= moderate and 15-21=severe).

Statistical Analysis: Frequency data were compared byusing the ‘chi’ square test. Mann Whitney test was usedfor comparing the scores (between cancer patients andhealthy individuals) on psychiatric rating scales. Thedifferences were considered significant if the ‘p’ valuewas less than 0.05. Statistical analysis was done usingSPSS.

RESULTS

The GHQ scores ranged from 0-11 in cancer patientswith a mean value of 3.7 while that of controls rangedfrom 0-6 with a mean value of 0.9800. The mean anxietyscore was 5.88 for cancer patients while those of controlswere 2.90. Likewise, the mean depression score of caseswas 6.64 while those of controls were 2.92. The

GHQ SCORES CANCER CONTROLSPATIENTS

0 05 291–2 15 13> 2 30 08TOTAL 50 50

Table-2: GHQ score distribution of subjects

X2= 18.72OR=7.88p= < 0.01(S)


Test Mean score of Mean score Mann Whitney Significancecancer patients of controls test

GHQ 3.7 0.9800 487.5 0.000 (S)ANXIETY 5.88 2.90 631.0 0.000 (S)DEPRESSION 6.64 2.92 458.0 0.000 (S)

Table-1: Psychological test results

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distribution of GHQ, depression and anxiety scores arepresented in Table-2, 3 and 4 respectively.

Anxiety, as identified by HADS, was found in 20(40.0%) of cancer patients. Out of 20 cancer patientswith anxiety, 14 (28.0%) had mild anxiety and 6 (12.0%)had moderate anxiety. Depression, as identified byHADS, was found in 14 (28.0%) of cancer patients. Outof 14 cancer patients with depression, 4 (8.0%) had milddepression, 8 (16.0%) had moderate depression and 2(4.0%) had severe depression.

Though a large number patient showed anxiety anddepression, a clinical diagnosis using ICD 10 criteriacould be given to 26% as against 4% of the control group(Table-5). The difference was statistically significant.Of the cancer patients who could be diagnosed, threehad Depressive Disorder, one had Anxiety Disorder, fivehad Adjustment Disorder and four had AlcoholDependence Syndrome.

DISCUSSION

General Health Questionnaire (GHQ): The GHQscores ranged from 0-11 in cancer patients with a meanvalue of 3.7 while that of controls ranged from 0-6 witha mean value of 0.9800 (Table-1). We could concludethat significantly higher percentage of cancer patients(60.0%) had psychiatric morbidity as compared tohealthy individuals (16.0%). GHQ scores distributionis presented in Table-2 and the difference was statisticallysignificant (p=<0.01). The odd that cancer patients hadpsychiatric morbidity is nearly 8 times more than thatof controls. A total of 30 (60.0%) were detected as ‘cases’based on a cutoff score of above 2 on 12 item GHQ.

The observed GHQ ‘caseness’ were within rangesreported in literatures viz: Akechi et al19 – 65.0%, Iqbalet al2 – 65.0%. But it was not consistent with reportedprevalence of 47.0% by Derogatis et al.20 In our study,the incidence of mental disorders among cancer patientswas slightly higher (60.0%) as compared to study byDerogatis et al.20 One possible explanation could be theattitude of patients towards their illness in our society.Due to lower literacy rate, people have a lot ofmisconceptions about cancer, such as cancer is incurable,cancer means death, etc. Even after getting necessary

and required information about the disease cancer andit’s treatment, they remain overanxious and uncertainabout their treatment outcome and their ability to copewith the illness.2 All the patients who were given apsychiatric diagnosis had abnormal scores on GHQgiving it a high sensitivity. Thus, GHQ –12 was foundto be good screening instrument for psychiatricmorbidity in cancer patients.

Depression: The depression score, in our study, rangedfrom 0 to 15 with a mean

value of 6.64 for the cases while those of controls rangedfrom 0 to 12 with a mean value of 2.92 (Table-1).Depression, as tested by HADS, was also found to bemore in the cancer patients (28.0%) than the controls(4.0%). Depression score distribution is presented inTable-3 and was statistically significant (p=<0.01). Theodd that cancer patients had depression is about 9 timesgreater than that of healthy individuals. Four (8.0%)patients had mild depression, eight (16.0%) hadmoderate depression and two (4.0%) had severedepression in the study. The distribution of depression(28.0%) in cancer patients, in this study, agrees withthat pointed out by Razavi et al,21 Hosaka et al22 andFulton.23 Razavi et al21 reported a 25.5% of depressionamong the referred patients and a similar proportion isobserved here. Hosaka et al22 reported depression to beseen in 28.0% of cancer patients.

Criteria for patient selection and methods of evaluationhave influenced the variation in values obtained and thatis why when comparing presently obtained figure of28.0% of cancer patients showing depression, agreementis not obtained with studies by Kathol et al24 – 19.0%,Berard et al25 – 14.0%, Akechi et al26 – 14.0%. Thisdiscrepancy, can be explained by the fact that differentscreening instruments (HRSD or and BDI) was used byKathol et al.24 They have reported diagnosis ofdepression differed as much as 13.0% depending uponthe diagnosis system used. Furthermore, Berard et al25

had initially used HADS and then the patients weresubsequently subjected to BDI and then to structuredpsychiatric interview. This may be one reason for lowestimates of depression on those studies.

P Thapa et al

DEPRESSION CANCER CONTROLSSCORE PATIENTS0–7 (No Depression) 36 488–10 (Mild) 04 0011–14 (Moderate) 08 0215–21 (Severe) 02 00TOTAL 50 50

Table-3: Distribution of depression scores of subjects

X2= 9OR=9.33p= < 0.01(S)

ANXIETY SCORE CANCER CONTROLSPATIENTS0–7 (No Anxiety) 30 488–10 (Mild) 14 0211–14 (Moderate) 06 0015–21 (Severe) 00 00TOTAL 50 50

Table-4: Distribution of anxiety scores of subjects

X2= 16.84OR = 16p= < 0.01(S)

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Anxiety: The mean anxiety scores, in our study, rangedfrom 0 to13 in cases

with a mean value of 5.88 while those of controls rangedfrom 0-8 with a mean value of 2.90 (Table-1). Anxiety,as identified by HADS, was found in 40.0% of the cancerpatients as against 4% for the control group. Thedifference was statistically significant (p=<0.01).Anxiety score distribution is presented in Table-4. Theodd that cancer patients had anxiety is 16 times morethan that of controls. Fourteen (28.0%) had mild anxiety,six (12.0%) had moderate anxiety and none had severeanxiety.

The distribution of anxiety in cancer patients (40.0%)agrees with that pointed out by Zeigler et al27 who hasalso reported 40.0%, but differences are seen as pointedout by most of the other studies. Other studies havereported anxiety as follows: Pinder et al28 – 25.0%,Kissane et al29 - 8.6%, and Pascoe et al30 - 11.5%. Thisdiscrepancy can be explained by the fact that both Pinderet al28 and Pascoe et al30 had used a cutoff of 11 or abovein the HADS whereas the present study has used thecutoff of above seven. The present study also identified6 (12.0%) individuals with anxiety had the cutoff beentaken as 11 or above. This would have been in agreementwith results quoted by aforementioned studies.Furthermore, study by Kissane et al29 used DSM IVdiagnostic criteria to come to a diagnosis of an anxietydisorder and obviously the element of interviewer biascannot be ruled out. The lack of knowledge about thedisease and its treatment may be considered as one ofthe causes of higher anxiety in our cancer patients.

SUMMARY AND CONCLUSION

The diagnosis of cancer carries with it a significantamount of psychological morbidity, both subjectivelyexperienced and objectively observed. Cancer treatments(chemotherapy and radiotherapy) further aggravatematters by becoming additional stressors. The presentstudy was carried out to assess and compare psychiatricmorbidities in cancer patients and healthy individuals.All patients were assessed by means of clinical interviewand psychological tests.

Results of the study showed (1) A total of 30 (60.0%)were detected as ‘cases’ or having psychiatric morbiditybased on a cutoff score of above 2 on 12 item GHQ,(2) Cancer patients had statistically significant higherGHQ scores (mean 3.7) as compared to controls (mean0.9800), (3) Both anxiety (40.0%) and depression(28.0%) were significantly higher in cancer patients thanthe controls and the two tended to go together and(4) A significant (p=<0.05) proportion, i.e. 26.0% cancerpatients could be given a diagnostic category using ICD10 DCR.

The impact of cancer produces a great deal of psychiatricmorbidity. Psychiatrists can play very important role inan integrated oncology treatment team by providingspecialized treatment which will not only reducepsychiatric morbidity but also result in improvement inoverall quality of life of cancer patients.

REFERENCES

1. Lesko LM. Psychological Issues. In: Devita VT Jr, HellmanS, Rosenberg SA, editors. Cancer. Priciples and Practice ofOncology. 5th ed. Philadelphia: Lipincott- Raven, 1997;2879-91.

2. Iqbal A, Syed GMS, Siddiqui KS. Mental disorders in cancerpatients: observations at a tertiary care center in Pakistan:Pak J Med Sci 2002; 18: 109-16.

3. Rouhami M, Holland JC. Psychiatric aspects of cancer. In:Gelder MG, Lopez-Ibor JJ, Andreason N, editors. New OxfordTextbook of Psychiatry.1st ed. New York: Oxford UniversityPress 2000; 1178-84.

4. Carvalho MM. Psycho Oncology: History, characteristic andchallenge. Psicol USP 2002; 13: 151-66.

5. Holland JC. History of Psycho Oncology: Overcomingattitudinal and conceptual barriers. Psychosom Med 2002;64: 206-21.

6. Holland JC. Psychological care of patients: PsychoOncology’s contribution. J Clin Oncol 2003; 21 (23 suppl) :253s-65s.

7. Greer S, Silberfarb P. Psychological concomitants of cancer;current state of research. Psychol Med 1982; 12: 563-73.

8. Goldberg R, Cullen L. Factors important to psychosocialadjustment to cancer; a review of the evidence. Social SciMed 1985; 20: 803-7.

9. Noyes R, Kathol RG. Depression and cancer. Psychiatr Dev1986; 2: 77-100.

10. Rodin GM, Voshart K. Depression in the medically ill: Anoverview. Amer J Psychiatr 1986; 143: 696-705.

11. Weissman A, Worden J. The existential plight in cancer:Significance of the first 100 days. Psychiatr Med1976; 7: 1-15.

12. Bukberg J, Penman D, Holland JC. Depression in hospitalizedcancer patients. Psychosom Med 1984; 46: 199-212.

13. Noyes. Distress associated with cancer as measured by theIllness Distress Scale. Psychosomatics 1990; 31: 321-30.

14. Maguire P. Psychiatric problem in the first year followingmastectomy. Brit Med J 1978; 1: 963-5.

15. Wells KB, Golding JM, Burham MA. Psychiatric disordersin a sample of general population with or without medicalconditions. Amer J Psychiatr 1998; 52: 100-13.

CANCER CONTROLPATIENTS(50) SUBJECTS(50)

Depressive disorders 3 1Anxiety Disorders 1 0Adjustment disorder 5 0Alcohol dependence 4 1syndrome

Table-5: Psychiatric diagnosis as per ICD 10 of cancerpatients and control

X2= 7.84

p= <0.05(S)


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16. Holland JC. Principles of Psycho Oncology. In: Holland JF,Frei F (Eds). Cancer Medicine. 4th Ed. Baltimore, MD:Williams and Wilkins, 1996: 1327-43.

17. Goldberg. The detection of psychiatric illness byquestionnaire. Maudslay Monograph No 2. London: OxfordUniversity Press, 1972.

18. Zigmond AS, Snaith RP. The hospital anxiety and depressionscale. Acta Psychiatr Scand 1983; 67: 361-70.

19. Akechi T, Okamura H, Nishiwaki Y et al. Psychiatricdisorders and associated predictive factors in patients withunresectable non-small cell lung carcinoma: A longitudinalstudy. Cancer 2001; 92: 2609-22.

20. Derogatis LR, Morrow GR, Fetting J et al. The prevalenceof psychiatric disorders among cancer patients. J Amer MedAssoc 1983; 249: 751-7.

21. Razavi D, Delvavx N, Farvacqes C et al. Screening foradjustment disorders and major depressive disorders in cancerpatients. Brit J Psychiatr 1990; 156: 79-83.

22. Hosaka T, Aoki T. Depression among cancer patients.Psychiatry Clin Neurosci 1996; 50: 309-12.

23. Fulton C. The prevalence and detection of psychiatricmorbidity in patients with metastatic breast cancer. Eur J

Cancer Care (England) 1998; 7: 232-9.24. Kathol RG, Mutgi A, Williams J. Diagnosis of major

depression in cancer patients according to four sets of criteria.Amer J Psychiatr 1990; 147: 1021-4.

25. Berard RM, Boermeester F, Viljoen G. Depressive disordersin an outpatient oncology setting: Prevalence, assessment,and management. Psycho Oncol 1998; 7: 112-20.

26. Akechi T, Nakano T, Okamura H et al. Psychiatric disordersin cancer patients. Descriptive analysis of 1721 psychiatricreferrals at two Japanese care center hospitals. Japanese JClinical Oncol 2001; 31: 188-94.

27. Zeigler G, Muller F. Prevalence and etiology of mentalproblems in tumor patients. Onkologie 1986; 9: 18-26.

28. Pinder KL, Ramirej AJ, Black ME et al. Psychiatric disordersin patients with advanced breast cancer; prevalence andassociated factors. Eur J Cancer 1993; 29A: 524-7.

29. Kissane DW, Clarke DM, Ikin J et al. Psychological morbidityand quality of life in Australian women with early stage breastcancer: a cross sectional study. Med J Aust 1999; 170: 239-40.

30. Pascoe S, Edelman S, Kidman A. Prevalence of psychologicaldistress and use of support services by cancer patients atSydney Hospitals. Aust NZ J Psychiatr 2000; 34: 785-91.

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Changing routes of hysterectomy : a cross sectionaland comparative study

NS Shrestha, R Saha and C KarkiDepartment of Ob/Gyn, Kathmandu Medical College Teaching Hospital, Kathmandu, Nepal

Corresponding author: Dr. Nira Singh Shrestha, Assistant Professor, Department of Ob/Gyn,Kathmandu Medical College Teaching Hospital, Kathmandu, Nepal; e-mail: [email protected]

ABSTRACT

Hysterectomy is one of the most frequently performed major surgical procedure in women. Traditionally, theuterus has been removed either by abdominal or vaginal route. In spite of the recommendations in favor ofvaginal hysterectomy majority of the hysterectomies are still done by the means of abdominal route and vaginalroute is utilized mostly for prolapsed uterus. This study was done to see the current trend of routes of hysterectomyfor benign condition at Kathmandu Medical College Teaching Hospital and its indication. This was a cross-sectional and comparative study done for 24 months (Jan 2008- Dec 2009). Data for the year 2009 was collectedprospectively and for the year 2008 case notes of all the cases of hysterectomy was reviewed. Total 317 casesof hysterectomy were done for benign condition in KMCTH during the 2 year study period. Of the 317 cases124 was done during the year 2008 and 193 during 2009. Three major route namely vaginal hysterectomy(VH), Abdominal Hysterectomy (AH), and Laparoscopic hysterectomy (LH) was utilized for performinghysterectomy. Major indication for hysterectomy was pelvic organ prolapse (POP) followed by abnormaluterine bleeding (AUB), and fibroid uterus during both the years. Route of hysterectomy in the cases with nonprolapsed pelvic organ were AH (94.0%) and LH (6.0%) during the year 2008 and VH (6.0%), AH (76%) andLH (18.0%) during the year 2009. Major indications for hysterectomy are POP, AUB, and fibroid uterus. VHis mainly done for the cases of POP. AH is still the major route for indications other than POP. Minimallyinvasive approach like VH for non descent uterus and LH although is rising needs to be practiced more.Keywords: Routes of hysterectomy, laparoscopic hysterectomy, abdominal hysterectomy, vaginal hysterectomy.

INRTODUCTION

Hysterectomy is, after Caesarean delivery, one of themost frequently performed major surgical procedure inwomen.1 Traditionally, the uterus has been removedeither by abdominal or vaginal route. Laparoscopicassisted vaginal hysterectomy gained its popularity in1990s and gynecologist in developed country startedopting for laparoscopic hysterectomy (LH) in the placeof abdominal hysterectomy (AH).2 New approaches liketotal laparoscopic hysterectomy and robotic-assistedvaginal hysterectomy have also emerged in recent days.3,4

In a recent meta-analysis to evaluate the most appropriateapproach to hysterectomy 27 trials were reviewed.5 Thismeta-analysis on the basis of significant speedier returnto normal activities and improvements in terms of othersecondary outcomes (shorter duration of hospital stayand fewer unspecified infections or febrile episodes)suggest that vaginal hysterectomy (VH) is preferable toAH, provided it can be performed safely. Where VH isnot possible, LH may help to avoid AH, but the formerconfers a greater chance of bladder or ureteral injury.5

A recent Cochrane review of surgical approach forbenign gynaecological disease, involving 4495 women

in 34 trials, concluded that the vaginal approach ispreferred to the abdominal approach. When vaginalhysterectomy is not possible, laparoscopic hysterectomymay avoid the need for an approach by laparotomy.6

ACOG recommendation regarding routes ofhysterectomy for benign indications is also similar.7

In spite of the recommendations in favor of vaginalhysterectomy majority of the hysterectomies are stilldone by the means of abdominal route and vaginal routeis utilized mostly for prolapsed uterus. Currently in theUnited States, about 64% of hysterectomies for benigndisease are performed abdominally, about 22.0% areperformed vaginally, and about 14.0% are performedlaparoscopically.8 In Sweden nearly 70.0% of thehysterectomy for benign indications are done byabdominal route.9

This study was done to see the current trend of route ofhysterectomy for benign condition at KMCTH and itsindication, to compare the routes of hysterectomy forbenign conditions between the year 2008 and 2009, andto find out the proportion of hysterectomy done in aminimally invasive approach.


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This was a Cross sectional and comparative study donein the department of Obstetrics and gynaecology,KMCTH for the period of 24 months from January 2008to December 2009. Data for year 2009 was collectedprospectively and for the year 2008 charts of the casesof hysterectomy were reviewed. Cases of hysterectomydone for malignancy and emergency obstetrichysterectomy were excluded from the study as theseindications mandate abdominal route. For each cases ofhysterectomy done for benign condition data werecollected on characteristics like age, indication ofhysterectomy, and route of hysterectomy. Data wereentered into a computer database using Microsoft Excelspreadsheet and statistical analysis was performed.Results are presented as frequencies, percentages anddescriptive statistics.

RESULTS

Total hysterectomy for benign indication during the 24months study period was 317.

Out of this 124 was done in the year 2008 and 193 in theyear 2009. Three major route namely vaginalhysterectomy (VH), Abdominal Hysterectomy (AH),and Laparoscopic hysterectomy (LH) was utilized forperforming hysterectomy. Mean age for AH was 46.33years, for VH- 57.22 years, and LH- 46.41 years. Majorindication of hysterectomy was pelvic organ prolapse(POP), abnormal uterine bleeding (AUB), and fibroiduterus (Table-1).

Route of hysterectomy in majority of the cases were AHfollowed closely by VH during both the years. All of theVH during the year 2008 were for POP, and most of the

VH during the year 2009 also was for POP. Total numberof cases operated by LH increased in 2009 (Table-2).

Routes of hysterectomy for indication other thanprolapse in year 2008 were mainly AH (94.0%) and LHwas done only in 4 cases (6.0%). In the year 2009 nondescent VH was also done in addition to the AH and LH.

Route of hysterectomy in the 125 cases with conditionsother than prolapse in year 2009 were VH in 8, AH in94, and LH in 23 (Table-3).

Minimally invasive surgery (MIS) like non descent VHand LH was done only in 6.0% of the cases during theyear 2008 (Fig. 1). The proportion of MIS increased to25.0% during the year 2009 (Fig. 2).

DISCUSSION

This study shows that majority of the hysterectomy wasdone for the pelvic organ prolapse, followed by abnormaluterine bleeding, and fibroid uterus. The indication forhysterectomy in developed countries like USA andEuropean countries are mainly fibroid uterus,dysfunctional uterine bleeding, endometriosis and pelvicpain and only a small percentage of hysterectomies areperformed for pelvic organ prolapse.10,11 The differencein the indication can be explained by the fact that Nepalhas a very high prevalence POP.12 Second commonestindication for hysterectomy in this study was abnormaluterine bleeding as alternative modalities of treatmentfor menorrhagia like endometrial ablation, and Uterineartery embolization are not practiced in Nepal.

During the study period routes of hysterectomy wasmainly AH (49.0%), VH (42.0%), and LH (9.0%).Majority of the VH was done for POP.

In the indication other than POP 82.0% of thehysterectomy was AH, 14.0% was LH and only 4.0%was VH. This trend in route of hysterectomy for benignindications are similar to the trend in developed countrylike USA where 64.0% of the hysterectomy are AH,22.0% VH, and 14.0% LH.8 In Sweden 80.0% of thehysterectomy done for benign indication are AH.

In the year 2008 VH was done only for prolapsed uterus,and majority of the non prolapsed uterus was operatedvia abdominal route. This trend reflects the mindset of

NS Shrestha et al

Routes Year 2008 Year 2009 TotalVH 57 (46.0%) 76 (40.0%) 133 (42.0%)AH 63 (50.8%) 94 (48.0%) 157 (49.0%)LH 4 (3.2%) 23(12.0%) 27 (9.0%)Total 124 (100%) 193 (100%) 317 (100%)

Table-2: Routes of hysterectomyRoutes Year 2008 Year 2009 TotalVH x 8 (6.0%) 8 (4.0%)AH 63 (94.0%) 94 (76.0%) 157 (82.0%)LH 4 (6.0%) 23 (18.0%) 27 (14.0%)Total 67 (100%) 125 (100%) 192 (100%)

Table-3: Routes of hysterectomy-non descent uterus

Indications Year 2008 n=124 Year 2009 n=193POP 59 (47.6%) 68 (35.0%)AUB 28 (22.6%) 49 (26.0%)Fibroid 28 (22.6%) 44 (24.0%)Ovarian cyst 6 (4.8%) 22 (11.0%)Cx dysplasia 3 (2.4%) 6 (2.2%)Others X 4 (1.8%)

Table-1: Indications of hysterectomy

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VH is the least invasive approach to hysterectomy, andits use should be encouraged as the preferred MIS(minimally invasive surgery) option for women requiringhysterectomy for benign conditions.

ACKNOWLEDGEMENTSI am thankful to our patients without whom this study wouldnot have been possible. I am also thankful to all facultymembers and staffs of department of Obstetrics &Gynaecology of the KMCTH for preparing this study

REFERENCES

1. Wilcox L, Koonin L, Pokras R, Strauss L, Xia Z, Peterson H.Hysterectomy in the United State 1998-90. Obstet Gynecol1994; 83: 549-55.

2. Reich H, DeCaprio J, McGlynn E. Laparoscopichysterectomy. J Gynecol Surg 1989; 5: 213-6.

3. Chapron CM, Dubuisson BJ, Ansquer Y. Is total laparoscopichysterectomy a safe surgical procedure? Human Reprod 1996;11: 2422-4.

4. Reynolds RK, Advincula AP. Robot-assisted laparoscopichysterectomy: technique and initial experience. Amer J Surg2006; 191: 555-60.

5. Johnson N, Barlow D, Lethaby A, Tavender E, Curr L, GarryR. Methods of hysterectomy: systematic review and meta-analysis of randomized controlled trials. Brit Med J 2005;330: 1478.

6. Nieboer TE, Johnson N, Lethaby A et al. Surgical approachto hysterectomy for benign gynaecological disease. CochraneDatabase Syst Rev 2009; 8: CD003677.

7. ACOG Committee Opinion No. 444: Choosing the route ofhysterectomy for benign disease. Obstet Gynecol 2009;114: 1156-8.

8. Jacoby VL, Autry A, Jacobson G, Domush R, Nakagawa S,Jacoby A. Nationwide use of laparoscopic hysterectomycompared with abdominal and vaginal approaches. ObstetGynecol 2009; 114: 1041-8.

9. Lundholm C, Forsgren C, Johansson AL, Cnattingius S,Altman D. Hysterectomy on benign indications in Sweden1987-2003: a nationwide trend analysis. Acta Obstet GynecolScan 2009; 88: 52-8.

10. Carlson KJ, Nichols DH, Schiff I. Indications forHysterectomy. New Engl J Med 1993; 328: 856-60.


Fig. 2. Minimally Invasive Surgery-2009Fig. 1. Minimally Invasive Surgery-2008

the gynecologist who are trained to do VH only for POP.However, in the year 2009, VH was introduced also forthe non prolapsed uterus. The reason behind this changein attitude is increasing experience with LH which gavesurgeons the skill and confidence to do VH even for nonprolapsed uterus. In recent times large volume of data areavailable on the feasibility of removing a nonprolapseduterus vaginally.13-15

All the traditional contraindication like vaginalnarrowing, inaccessibility of the uterus,

Lack of uterine descent, larger uterine volume,nulliparity, and previous ceasarean delivery are no longerconsidered as contraindication for vaginal hysterectomy.In our experience even during our initial phase ofnondescent vaginal hysterectomy we have managed todo successful vaginal hysterectomy for large fibroiduterus with uterine size upto 20 weeks size, nulliparousuteri, and with history of previous caesarean delivery.

Most of the current recommendation favor minimallyinvasive surgery like VH over AH.5-7 In the developingcountry like Nepal feasibility and acceptability of nondescent VH should be high as this procedure does notrequire expensive instruments and learning curve of thisprocedure is very short.13 It will also prove economicalfor the low resource country like Nepal. To increase thepercentage of hysterectomy done by minimally invasiveroute like VH, making vaginal route as norm whenplanning hysterectomy for benign indication can be useful.This approach has been proven effective in a study doneby Varma et al where rate of vaginal hysterectomyincreased from 32.0-95.0% in just five years time.13

Major indication for hysterectomy was POP, AUB, andFibroid uterus. AH was the major route of hysterectomyfor indication other than prolapse. VH was typically utilizedfor pelvic organ prolapse. Trend is rising towards minimallyinvasive approach like non descent VH and LH.

75%

25%

94%

6% AHMIS

AHMIS

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11. Debodiance P. Hysterectomy for benign lesions in the northof France: epidemiology and postoperative events. J GynecolObstet Biol Reprod (Paris) 2001; 30(2):151-9.

12. Bonetti T R. Erpelding A, Pathak LR. “ReproductiveMorbidity- a neglected issue? A report of a clinic based studyheld in Far-WesternNepal” Kathmandu, Nepal: Ministry ofHealth, GTZ and UNFPA.2002; chapter 4: 26-30.

13. Verma R, Tahseen S, Lokugamage AU, Kunde D. Vaginalroute as the Norm When Planning Hysterectomy for Benign

Conditions: Change in Practice. Obstet Gynecol2001; 97: 613-6.

14. Sheth SS. Vaginal hysterectomy. In: Studd J, ed. Progress inObstetric and Gynaecology. Vol. 10. Edinburgh, UK:Churchill Livingstone; 1993: 317-39.

15. Unger JB. Vaginal removal of the benign non-prolapseduterus: Experience with 300 consecutive operations. Amer JObstet Gynecol 1999; 180: 1337-44.

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An evaluation of pulmonary parameters in two groups of subjectsduring Yoga practice

QR Ahmed,1 SK Sau2 and SK Kar3

Department of Physiology, 1Rohilkhand Medical College and hospital, Bareilly, Uttar Pradesh, India, 2Institute of Dental Sciences,Bareilly, Uttar Pradesh, India, 3Universal College of Medical Sciences, Paklihawa Campus, Bhairahawa, Lumbini, Nepal

Corresponding author: Dr. Sanjit Kumar Kar MSc, PhD, Associate Professor, Department of Physiology, Universal College of MedicalSciences, Paklihawa Campus, Bhairahawa, Post Box: 53, Lumbini Zone, Nepal;

e-mail: drkarsk @rediffmail.com / [email protected]

ABSTRACT

The purpose of the present study was to investigate how far the short term practice of yoga (30 and 60 days) foran hour daily can improve the respiratory function. Male subjects (n=50, age 30-50 years) were randomlyselected. Respiratory parameters (FVC, FEV1, PEFR, FEF25-75% and MVV) were determined by using amultifunctional computerized spirometer. Yoga (posture and pranayamas) practice for a month produced nosignificant improvement in pulmonary parameters. Nevertheless, when the subjects continued it for next 30days, i.e., after 60 days significant changes were noted in FVC (p<0.001), FEV1 (p<0.01) and PEFR (p<0.05).The result also revealed that amongst them 30 days yoga training resulted in a significant increase in FVC inelder group of people (age 41-50 yrs) where as in younger group (age 30-40 yrs) the changes were not soprominent. Result indicated that short term (30 days) yoga practice quickly improves respiratory functions inrelatively elder people (age 41-50 yrs), when many of them in our tropical country suffer from primary level ofrespiratory problem. Regular practice of Yoga (posture and pranayamas) can prevent it by increasing theefficacy of respiratory muscles.Keywords: Yoga, pranayama, breathing exercises, FVC, FEV1, PEFR.

INTRODUCTION

Yoga is popular all over the world nowadays. It increaseslongevity,1 and has therapeutic and rehabilitative effects.2-5

Yoga techniques include the practice of meditation, avariety of breathing exercises, and the practice of anumber of physical exercises and postures, in which thefocus is more on isometric exercise and stretching thanon aerobic fitness.6

Pranayama is an important component of yoga training.Pranayama (controlled breathing exercise) improves theair way reactivity in the asthmatic individuals.7 It wasnoted that high frequency breathing exercise resulted inmore than 10 fold increase in expired minute ventilation.8Many reports supported the beneficial effect of long-term yoga training on pulmonary functions.9-11

It has been reported that yoga practice an hour/day, for12 weeks resulted significant increment in the forcedvital capacity (FVC), forced expiratory volume in 1st

second (FEV1) and peak expiratory flow rate (PEFR).12

Yoga was proved to be helpful for bronchial asthma.13

In a study with subjects between the ages of 40 to 60yearswith no previous yoga experience, 80.0% showedimprovement in breath holding time after the completionof an intensive yoga program.14

The purpose of the present investigation was todetermine how far yoga practice over a short durationof 60 days for an hour daily can improve respiratoryfunction.


The present study was conducted in Department ofPhysiology of Rohilkhand Medical College and Hospitalwith the collaboration of Yoga center of Bareilly, U.P., India.

New comer male subjects (age 30-50 years) wereselected randomly from the yoga center of Bareilly,practicing yoga regularly. The subjects were priorlyinformed about the study and the consents were taken.They were divided in to two age groups: Gr. - A (30-40yrs, n=25) and Gr.- B (41-50 yrs, n=25).

The pulmonary function tests or respiratory capacity ofthe subjects were determined using a multifunctionalcomputerized spirometer (Sl. No. A-23-050.0883).Forced Vital Capacity (FVC), Forced Expired Volume-1st-- sec. (FEV1), Peak Expiratory Flow Rate (PEFR),Forced Expiratory Flow (FEF25-75%) and MaximumVoluntary Ventilation (MVV) were measured.

The subjects were asked to take a deep breath and blow itinto the mouth piece of the spirometer. A nasal clip was


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used to close the nose to prevent the air flow through thenostrils. Before taking the reading they were instructedto do the same 2 - 3 times for the better expiration. Theywere asked to practice the yoga (posture and pranayamas)regularly and the data on the same parameters werecollected after 30 days and 60 days interval.

Data were analyzed with the help of a software packageon ‘Statistical’ (Version 6.0). The ‘t’-test and ‘p’ valuesamong different groups of parameters were done.

RESULTS

The all pulmonary parameters which were taken beforeand after 30 days and 60 days of yoga practice of the allsubjects are presented in the Table-1 which indicatedthat 30 days of yoga practice produced no significantchange in pulmonary parameters. Nevertheless, whenthe subjects continued it for next 30 days, i.e., after 60days significant changes were noted in FVC (p<0.001),FEV1 (p<0.01) and PEFR (p<0.05).

The results also revealed a significant increase in FVC

(p<0.001) in Group B (age 41-50 yrs) after30 days training as well as after 60 dayswhereas in Group A (age 30-40 yrs) thesignificant changes were noted only after 60days of Yoga (posture and pranayamas)practice.

DISCUSSION

Yoga practice causes betterment ofpulmonary functions. Studies revealed thebeneficial effect the yoga on cardiorespiratory function of school children15 butthe increase in FVC and FEV1 in the groupwas statistically insignificant. PEFR

increased significantly in the Yoga and fast and slow‘Suryanamaskar’ groups.

Our findings are consistent with those studies whichnoted an increase in FVC, FEV1 and PEFR after yogatraining.16,12 Short term ‘pranayama’ ( six week course)resulted in increased FVC and FEV1 which might bedue to strengthening of the respiratory musculature withthe regular practice of the Yoga.17,18

With the advancement of the age the strength of therespiratory musculature decreases and the normalexpansion of the chest does not occur. Result revealedthat the respiratory parameters are significantly increasedin Gr.-B after 30 days of yoga practice and the significantdifference also noted in Gr.-B after 60 days. Earlierstudies also supported that short term yoga practice (tenweeks course) recorded improved respiratory functionsin the form of lowered respiratory rate, increased forcedvital capacity, maximum breathing capacity and breathholding time, while tidal volume and FEV1, did notreveal any significant change.16

QR Ahmed et al

Table-1: Pulmonary parameters before and after YogaPulmonary All Subjects (n=50)Parameters

Before Yoga After 30 days After 60 days(Mean± SD) Yoga (Mean± SD) Yoga (Mean± SD)

FVC (l) 2.33 ±0.73 2.58 ±0.56 2.79 ±0.53*FEV1 (l) 1.92 ±0.36 2.00 ±0.37 2.14 ±0.35**FEV1/FVC (%) 77.72 ±12.33 82.22 ±15.81 82.51 ±15.39PEFR (l min-1) 4.82 ±1.73 5.31 ±1.44 5.59 ±1.59***FEF25-75 (l) 2.66 ±0.98 2.85 ±0.84 2.89 ±0.77MVV (l min-1) 88.92 ±30.65 90.10 ±27.05 93.77 ±26.85

* P<0.001 ** P<0.01 *** P<0.05

* Indicate within group w.r.t. before yoga * p<0.05 ** p<0.001 ***p<0.02^ Indicate between groups with respect to before yoga ^ p<0.001 ^^ p<0.01$ Indicate between groups with respect to after 30 days yoga $ p<0.001# Indicate between groups with respect to after 60 days yoga # p<0.001 ## p<0.02 ### p<0.01

Age Gr. (yrs)Gr.-A (30-40 yrs, n=25) Gr.-B (41-50 yrs, n=25)

Pulmonary Parameters Before Yoga After 30 days After 60 days Before Yoga After 30 days After 60 days(Mean± SD) Yoga (Mean± SD) Yoga (Mean± SD) (Mean± SD) Yoga (Mean± SD) Yoga (Mean± SD)

FVC (l) 2.77 ±0.62 2.93 ±0.41 3.10* ±0.42 1.89^ ±0.54 2.24***$ ±0.48 2.48**# ±0.45FEV1 (l) 2.10 ±0.28 2.25 ±0.26 2.35** ±0.20 1.75^ ±0.36 1.75$ ±0.29 1.93# ±0.34FEV1/FVC (%) 72.44 ±11.27 77.91 ±11.72 77.10 ±11.16 83.00^^ ±11.19 86.53 ±18.29 87.92## ±17.27PEFR (l min-1) 5.66 ±1.77 6.00 ±1.55 6.62* ±1.51 3.98^ ±1.22 4.62*$ ±0.91 4.56# ±0.81FEF25-75 (l) 3.08 ±1.01 3.25 ±0.89 3.25 ±0.81 2.24^^ ±0.76 2.45$ ±0.56 2.54# ±0.53MVV (l min-1) 102.59 ±25.75 104.38 ±24.58 105.60 ±24.42 75.26^ ±29.44 75.83$ ±21.59 81.95### ±24.19

Table-2: Pulmonary parameters before and after yoga between two age groups

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Study of Pathak et al. indicated subjects performing‘Pranayama’ though a little older in age than matchedcontrol group, preserved their body in better frame,remained more proportionate with respiratory functionsand exhibited stronger grip strength.19

Present study indicated that short term (30 days) Yogapractice (posture and pranayamas) is beneficial mainlyin elder group of people (age 41-50 yrs) when manypeople in our tropical country suffer form primary levelof respiratory problems. Regular practice of Yoga canprevent it by increasing the efficacy of respiratorymuscles.

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2. Datey KK, Deshmukh SN, Dalvi CP, Vinekar SL. “Savasana”and Yogic exercise in the ‘management of hypertension’.Angiology Research Foundation, Las Vegas 1969; 325-33.

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17. Joshi LN, Joshi VD, Gokhale LV. Effect of short term‘pranayam’ practice on breathing rate and ventilatory functionsof lung. Indian J Physiol Pharmacol 1992; 36: 105-8.

18. Joshi LM, Joshi VD. Effect of forced breathing on ventilatoryfunction of the lung. J Postgrad Med 1998; 44: 67-9.

19. Pathak JD, Mehrotra PP, Joshi SD. A plea for ‘Pranayama’for elderly. Indian J Physiol Pharmacol 1978;22 (Suppl 4): 77-80.


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Age at menarche of subpopulation of Nepalese girlsL Sunuwar,1 CG Saha,2 Anupa KC3 and K Upadhyay Dhungel4

1Department of Physiology, Patan Academy of Health Sciences, Lalitpur, Nepal, 2Department of Physiology, Manipal College of MedicalSciences, Pokhara, Nepal, 3Department of Pharmacology, Patan Academy of Health Sciences, Lalitpur, Nepal,

4Department of Physiology, KIST Medical College, Lalitpur, Nepal

Corresponding author: Laxmi Sunuwar, Assistant Professor, Department of Physiology, Patan Academy of Health Sciences,Lalitpur, Nepal; e-mail: [email protected]

ABSTRACT

The present study was carried out to explore the mean age at menarche of school going girls of Western Nepal,Pokhara and to determine the factors influencing age at menarche. The data was collected from five schoolslocated within the Pokhara Valley of Western Nepal. Only the students who had experienced menarche wereincluded in the study. Verbal consent was obtained after explaining the objectives of the study; the studentswere interviewed for personal and family details and information obtained was recorded. The age at menarchewas found to be 12.69 ±0.95 years. The mean age at menarche of those attending community schools wassignificantly higher than that of those attending private schools (12.85 ±0.87 vs 12.41 ±0.99 years). The meanage at menarche was found to be delayed with increase in number of family members and more siblings. Themean age at menarche of the vegetarians was higher than that of non-vegetarians (12.82. ± 0.81 vs 12.68 ±0.95years).Keywords: Age at menarche, adolescent, western Nepal.

INTRODUCTION Menarche indicates the specific stage of first periodicalregular flow of blood from uterus in all healthy females.1

It is the most striking event in the process of femalepuberty, which in turn is a part of adolescence. Sequenceof events takes place throughout puberty - thelarche, thedevelopment of breasts, followed by pubarche, thedevelopment of axillary and pubic hair, and then bymenarche, the first menstrual period.2

Menarcheal age serves as an easily identifiable markerfor developmental status relative to same-age peers.Several reports are found stating that the females havingearly menarche have elevated risk for breast cancer.3,4

The age at menarche is not fixed, but varies frompopulation to population.5 It may also vary with races,size of the family and environmental factors.3,5-9 Fewreports have shown that age at menarche varies withpassage of time, occurring earlier than it did.9 However,literature about the age of menarche in Nepalesepopulation is scanty and hence, it is worth studying.Present study attempted to explore the age at menarcheand factors influencing it amongst the girls of WesternNepal, Pokhara.


The study sites were five schools located in the PokharaValley, Western Nepal. It was a cross-sectional studyfollowing non-probability sampling method. Datacollection was done for duration of four months (March

2006 to June 2006). The female students (n=450) of theselected schools who had already experienced menarcheas well as those who were facing secondary amenorrheaat the time of study were included. The girls werepersonally interviewed for the required information(monthly income, earner’s occupation, menarche age ofmother and eldest sister etc).

The data thus collected was analyzed using statisticalpackage for the social sciences (SPSS Version 10.0) andMS-Excel. Independent-samples t-test was used todetermine the significance level of the difference in meanage at menarche. Non-parametric two-independent-samples test (Mann-Whitney U) was applied todetermine the significance level of the differences inage at menarche on the basis of type of school attended.

RESULTS

The age range of the participants was found to be 9-20years and the mean age at menarche was found to be12.69 ±0.95 years. The earliest occurrence of menarchewas found in a girl at the age of 9 years.

Fig. 1. shows the mean age at menarche of theparticipants (12.69 years), their mothers (14.80 years)and their eldest sisters (13.40 years). The differencebetween mean age at menarche among them was foundstatistically significant (p<0.001).

Table-1 shows the mean age at menarche according todietary habit. It was seen that the mean age at menarche


184

attending. The mean age atmenarche of the participantsattending private school wassignificantly higher (12.41±0.99 years) than that of theparticipants attendingcommunity school (12.85±0.87 years).

DISCUSSION

In the present study, the meanage at menarche of young girlsfrom Western Nepal, Pokharawas found to be 12.69 ± 0.95years. A study by Sharma et alshowed median age atmenarche of schoolgirls of

Dharan to be 12 years with agerange 11-17 years which was

slightly less than that of present study.10 In another studythe mean age at menarche of 239 girls from Palpa andRupandehi Districts was found to be 14.3 years.11 Thisdifference in mean age at menarche may be due toincreased urbanization of Dharan and Pokhara relativeto Palpa and Rupandehi. Increased urbanization can leadto better socio-economic status, more sedentary lifestyle,exposure to media and changes in dietary habits as wellas better psychological preparation all of which can havean effect in the age at menarche.5,8,9

The mean age at menarche of the students in the presentstudy was found to be lesser than that of their elder sisters(13.4 ±1.76 years) which was in turn lesser than that oftheir mothers, (14.8 ±1.67 years). This shows adescending pattern of age at menarche with successivegenerations. In a study carried out in Spain, mean age atmenarche in mothers, (13.45 ±1.51 years) wassignificantly (p<0.01) greater than in daughters (13.03±1.28 years).12 Similarly, the study by Ersoy et al showedthe mean menarcheal age of the mothers (13.6 ±1.39years) was higher than the mean menarcheal age of thedaughters 12.82 ±1.07 years, (P<0.001).13 Studies haveexplained such decrease in age at menarche withsuccessive generations as a result of increase in

urbanizationand environmental changes likebetter dwelling conditions, smaller familysize compared to previous generations, foodhabits and sedentary life styles of successivegeneration.3-5,8,9 Children today are exposedto television advertisements for high-fat andsimple-carbohydrate food and drinks. Also,activities like watching television withsnacks can be associated with sedentarylifestyle.14 This in turn is associated with

Fig. 1. Mean age at menarche of the participants, their mothers and their eldest sisters


of the vegetarian participants (n=17) was little higherthan that of non-vegetarians (n=433) [12.82 ±0.81 vs12.68 ±0.95 years].

Table-2 gives the comparison of the family size andnumber of siblings of the participants with their age atmenarche. It was seen that participants from a family offour or fewer members had a lesser age at menarche (at12.46 ±0.93 years) while that for participants from familieswith more than four members was found to be 12.76(±0.94) years. This result was significant statistically atp<0.005. Also, an increase in age at menarche was seenwith more number of siblings. The mean age at menarcheof the participants with only one or no siblings wassignificantly lower than that of those with more than onesiblings (12.36 ±0.86 vs 12.79 ±0.94 years).

Table-3 shows the difference between ages at menarcheof the participants according to type of school they were

Parameter N=450(%) Mean age at p valuemenarche(SD)

Dietary habit Vegetarian 17 (3.77) 12.82 (0.81) 0.544non-vegetarian 433 (96.22) 12.68 (0.95)

Table-1: Mean age at menarche according to dietary habit

Parameter N=450 Mean age at p value(%) menarche(SD)

Number of family 4 108 (24.00) 12.46 (0.93) <0.005members >4 342 (76.00) 12.76 (0.94)Number of 1 108 (24.00) 12.36 (0.86) <0.001siblings >1 342 (76.00) 12.79 (0.94)

Table-2: Mean age at menarche in relation to family size and numberof siblings

<

<

185

increasing body mass and body fat. The fat cells secreteleptin. Leptin can influence the synthesis and/or secretionof other hypothalamic peptides which in turn modulategonadotropin- releasing hormone (GnRH) release.15,16

Rise in GnRH leads to increased production ofgonadotropins (luteinizing hormone; LH and follicularstimulating hormone; FSH). Higher levels of FSH andLH causes resultant increase in estrogen level. Risinglevels of estrogens and pulsatile GnRH secretion leadsto initiation of menses and eventuallly create cyclicmenstrual patterns causing early menstruation.17

In the present study, mean age at menarche of thevegetarian participants 12.82 (±0.81) years, was higherthan that of non-vegetarians which was 12.68 (±0.95)years. This result, however, was found to be statisticallyinsignificant (p=0.544). Similarly, many studies havereported the accelerating influence of good nutrition onpuberty from many parts of the world. These studieshad a common belief that the protein rich high caloriediet causes better physical maturation and earlymenarche.5,18,19 On the contrary a study carried out byPadmavati et al reported the delayed onset of menarcheof non-vegetarian girls.18 Also, in our study; comparisonwas limited by small sample size of vegetarianscompared to non-vegetarians.

The mean age at menarche in the current study was foundto be delayed with increase in number of family members(p<0.005) and siblings (p<0.001) and both results werestatistically significant. A study by Padez et al has alsoshown girls born in small families with one child maturedearlier than those born in large families with four or morechildren.7 Another study by Roberts et al found thatmenarcheal age is strongly influenced by family sizeand also partly by position in family i.e., menarcheoccurs later in large sibships.20,21 However, Salces et alfound no such significant contribution of birth order onthe age at menarche.12,22

The mean age at menarche of girls from private schoolswas lower than that of the girls from community school.Attending private school indicates better family income,which is also a component of socioeconomic status.However, the age at menarche of the participants in ourstudy could not be correlated with monthly familyincome as all the participants were not able to giveinformation regarding the monthly income of the family.

There are other components associated withsocioeconomic status (family size, living conditions,nutrition supplement) which are usually associatedpositively with early menarche.5,18,19 A study carried outin Nigeria showed that school girls from higher socio-economic class reached menarche earlier than the lowersocio-economic counterparts.23 In a similar cross-sectionstudy carried out on menarcheal age in 2087 Ghanaianschool girls, the menarcheal age (13.98 ±1.42 years) wasfound to be significantly influenced by social class,parents ethnic origin, educational institution and homeliving area.24 Nepalese evidence is consistent with theargument that menarcheal timing is associated withnutritional status where early maturing females comefrom richer family who enjoy a greater availability ofgood food than others.11 Another explanation accordinga report made by Danker Hopfe is that the degree ofurbanization, occupation and educational status ofparents, family income, dwelling conditions, as well asfamily size do not exert a direct influence on theoccurrence of the first menstruation. These areessentially ‘secondary’ factors, which are more or lessassociated with those factors that presumably have amore direct influence, such as nutritional condition andhealth status.9

Menarche is the most striking event in the process offemale puberty. Menarcheal age serves as a marker fordevelopmental status relative to same-age peers. Severalreports have also associated early menarche withincreased risk for morbid conditions like breast cancer.The mean age at menarche in our study was found to be12.69 ± 0.95 years. Higher age at menarche wasassociated with attending community school, largerfamily size and larger number of siblings. However, thisdata does not represent the whole Nepalese population.Larger studies regarding age at menarche need to becarried out in larger representative population.

ACKNOWLEDGEMENTSWe thank Mr. Shital Bhandary, assistant professor, departmentof Community Health Sciences, Patan Academy of HealthSciences for his invaluable help in statistical analysis.

REFERENCES

1. Biswas RK, Kapoor AK. Age at Menarche and MenopauseAmong Saharia Women –A Primitive Tribe of MadhyaPradesh. Anthropologist 2004; 6: 247-52.

2. Ayatollahi SMT, Dowlatabadi E, Ayatollahi SAR. Age atmenarche and its correlates. Southern Iran. Iran J Med Sci1999; 24: 20-5.

3. Trentham-Dietz A, Nichols HB, Remington PL et al.Correlates of Age at Menarche among Sixth Grade Studentsin Wisconsin. Winconsin Med J 2005; 104: 65-9.

4. Petriduo E, Syrigou E, Toupadaki N, Zavitsanosw X, Willett W,Trichopoulos D. Determinants of age at menarche as early lifepredictors of breast cancer risk. Int’l J Cancer 1996; 68, 193-8.

L Sunuwar et al

Type of school N=450 (%) Mean age at p value(SD) menarche

Private 166 (36.88) 12.41 (±0.99) <0.001Community 284 (63.11) 12.85 (±0.87)

Table-3: Relation of mean age at menarche and school type

186

5. Zacharias L, Wurtman RJ. Age at menarche. Genetic andenvironmental influences. New England J Med 1969;280: 868-75.

6. Thórdur Eydal Magnússon. Age at menarche in Iceland. AmerJ Physical Anthropol 2005; 48: 511-4.

7. Padez C, Rocha MA. Age at menarche in Coimbra (Portugal)school girls: a note on the secular changes. Annals HumanBiol 2003; 30: 622-32.

8. Pasquet P, Manguelle Dicoum Biyong A, Rikong Adie H,Befidi Mengu H, Garba MT, Froment A. Age at menarcheand urbanization in Cameroon: current status and seculartrends. Annals Human Biol 1999; 26: 89-97.

9. Deb R. Variation in the Age at Menarche of the Assameseand Bengali Girls of Guwahati, Assam. Anthropol 2009;11: 259-64.

10. Sharma M, Gupta S. Menstrual Pattern and Abnormalities inthe High School Girls of Dharan: A Cross Sectional Study inTwo Boarding Schools. Nepal Med Coll J 2003; 5: 34-6

11. Aryal TR. Age at menarche. Differentials and Determinants.J Nepal Med Assoc 2004; 43: 71-5.

12. Sanchez-Andres. Genetic and environmental factors affectingmenarcheal age in Spanish women. Anthropol-Anz 1997;55: 69-78.

13. Ersoy B, Balkan C, Gunay T, Egemen A. The factors affectingthe relation between the menarcheal age of mother anddaughter. Child Care Health Dev 2005; 31: 303-8.

14. Graham EA. Economic, Racial, and Cultural Influences onthe Growth and Maturation of Children. Pediaty Rev2005; 26: 290-4.

15. Cunningham Matthew J, Clifton Donald K, Steiner RobertA. Leptin’s Actions on the Reproductive Axis: Perspectivesand Mechanisms. Biol Reprod 1999; 60: 216-22.

16. Chan Jean L, Mantzoros Christos S. Leptin and thehypothalamic-pituitary regulation of the gonadotropin-gonadal axis. Pituitary 2001; 4: 87-92.

17. Gutyon AV, Hall JE. Textbook of Medical Physiology. 11th

edition. Philadelphia: Elsevier Saunders 2006; 1011-2.18. Rokade S, Mane A. A study of age at menarche, the secular

trend and factors associated with it. Internet J Biol Anthropol2009; 3: 1939-4594.

19. Asgharnia M, Faraji R, Sharami H, Yadak M, Oudi M. Astudy of menarcheal age in Northern Iran (Rasht). Oman MedJ 2009; 24: 95-8.

20. Roberts DF, Wood W, Chinn S. Menarcheal age in Cumbria.Ann-Hum-Biol 1986; 13: 161-70.

21. Robert M. Berne, Matthew N. Levy, Bruce M. Koeppen,Bruce A. Stanton. General Principles of EndocrinePhysiology; The Reproductive Glands. Physiology. 8th edition:St. Louis, Missouri: Elsevier; 2004.p. 726: 963.

22. Salces I, Rebato EM, Susanne C, San Martin L, Rosique J.Familial resemblance for the age at menarche in Basquepopulation. Ann Hum Biol 2001; 28: 143-56.

23. Abioye Kuteyi EA, Ojofeitimi EO, Aina OI, Kio F, Aluko Y,Mosuro O. The influence of socioeconomic and nutritionalstatus on menarche in Nigerian school girls. Nutr-Health1997; 11: 185-95.

24. Adadevoh SW, Agble TK, Hobbs C, Elkins TE. Menarchealage in Ghanaian school girls. Int’l J Gynaecol Obstet1989; 30: 63-8.


187

Common behaviour problems amongst primary school children in slumdwelling area of Kathmandu Valley

PP Kafle, L Vaidya, PP Panta , MR Chhetri and SK Mehrotra,Department of Community Medicine, Nepal Medical College Teaching Hospital, Attarkhel, Jorpati Kathmandu, Nepal.

Corresponding author: Dr. Phanindra Prasad Kafle, Department of community Medicine Nepal Medical College Teaching Hospital,Jorpati, Kathmandu, Nepal; e-mail: [email protected]

ABSTRACT

A cross sectional observation study was carried out in primary school children of slum dwelling area ofKathmandu Valley which included 454 students. The aim of study was to find out morbidity in habit disordersin age group of 6-10 years so that early detection will be helpful to correct them to prevent it from furtherpersonality maladjustment. There was no statistical difference in gender wise habit disorders. The morbidity isdue to multiple factors of physico- social environment. However severity of disease is not more herein this area.Keywords: Habits, disorder and primary school children.

INTRODUCTION

The study was carried on behaviour disorder morbiditypattern amongst primary school children in slum dwellingarea schools of Kathmandu valley which includes 454students of age between 6-10 years. The objective wereto collect health related information as behavior in childrenat primary school age and to study common behaviouralproblems which can be dealt at school level in relation topsychological aspect like behaviour, dental hygiene, eatinghabits and physical activity. Significant associations havebeen obtained consistently between learning disabilitiesand behaviour problems and various studies havesupported in other country.1

Extensive review of issues pertaining to the relationshipbetween externalizing behaviour problems and academicunderachievement, stated that, in childhood, inattentionand hyperactivity were stronger correlates of academicproblems than aggression.2

As children in primary school are vulnerable to anyinfection, similarly they adopt behavior disorders in thisage group. However it remains a cause of concern fortheir parents till they are grown up. Many times parentsdo not bother for such habits and later on they repent.Language and speech disorder are in school agepopulation and more prevalent in toddlers and pre-schoolbur it is not observed in our study. Similarly sleepdisorder is also not observed in any child.

Although the school age children morbidity is low inhabit disorder and behavior problems, which keep themaway from friends due to guilt feeling. In Nepal pooreconomic condition, inadequate infra structure ofmedical services inaccessibility to health services

declines the study environment in the school speciallyfor these children.


This study was conducted in NMC Hospital throughdepartment of community medicine whilesimultaneously carrying out school health survey in slumdwelling area of Kathmandu Valley. A predesigned semi-structured performa of questionnaire was prepared andpretested in one school to know the magnitude ofproblems in relation to behavior disorder and personalhygiene.

Data was analyzed on SPSS and excel soft ware. Povertyis a major underlying cause together with ignorance anda fatalistic attitude in familial environment. The teachersalso play the important part in observing the studentsand coordinating with parents’ level to time.

RESULTS

Common behaviour problems among primary schoolchildren 6-10 years of age were conducted in slumdwelling area of Kathmandu Valley. Total sample size ofthe study was 454. Among them 251 (55.3%) were maleand 203 (44.7%) were female. Out of the 454 children55 (12.1%) were felling nail biting, 35 (7.7%) thumbshucking, 27 (6.0%) bed wetting, 7 (1.5%) food fad, 16(3.2%) temper tantrum and 314 (69.2%) were none ofproblems (Table-1). Among them the bathing habits ofthe studied students were 266 (58.6%) once a week, 74(16.3%) twice a week, 21 (4.6%) thrice a week and 93(20.5%) regular bathing were found (Table-2). Thebrushing habits were found 333 (73.4%) once a day, 112(24.7%) twice a day and 9 (2.0%) regular (Table-3).


188

DISCUSSION

Our study subjects include 454 students in slum area ofKathmandu Valley. The minimum care by parents afterthe school hours prompted us to take up this study inthis developing country. In this study children aged lessthan 10 years were commonly affected. One hundredforty (40.8%) males were affected as observed here. Thisstudy revealed nail biting is a common behavior problemin the children of age group 6-10 years. Total 55 (12.1%)children found to have nail biting in male 20 (4.4%) andfemale 35 (7.7%) respectively as depicted in Table-1.Infected nail can lead to the skin diseases. This kind ofhabits can make parents, teachers or care taker as a causeof concern. When they became more conscious of theirappearance thumb shucking habit was found 35 (7.7%)next common disorder in this study. When they areanxious or lonely, they also immediately start thumbshucking. Food fad amongst school children is commonin 7 (1.5%) subjects only. How ever temper tantrum isalso observed in 16 (3.5%) students. None of behaviordisorders observed in 314 (69.2%) students which isremarkable in slum dwelling area. These are fewcommon adjustment disorders that are routinelydiagnosed during school health survey as it is in ourstudy. These disorders are mainly treated by educatingchildren and parents. Ritter 1989 also estimated socialcompetence with learning disability including childbehavior response.3

Social scientist can create a breach in such asocial habitsby detecting at early age and it can be corrected withhelp of clinical psychologist or psychiatrist in dealingwith behavior therapy. The childhood set up conductdisorder refers to a persistent pattern of anti-socialbehavior in which individual repeatedly breaks socialrules and carried out such acts that upset other people.The ratio of males to females with childhood disorder islower among Indian children.4

The range of disorders may be caused by a number offactors such as parenting style which is inconsistent orcontradictory, family or marital problems, child abuseor neglect, overindulgence, injury or chronic illness,separation or bereavement.5

Anxiety and fearfulness are part of normal developmenthowever, when they persist and become generalised theycan develop into socially disabling conditions andrequired intervention. Approximately 6.7% of childrenmay develop anxiety disorders and of this 1/3rd may beover anxious while 1/3rd may have some phobia.Generalized anxiety disorder childhood one set socialphobia, separation anxiety predictably cause by certainsituation. School phobia occurs in 1-2% of children ofan estimated 75.0% may be suffering some degree ofdepression and anxiety.6 The prevalence of childhooddisorder is 11.1% in Indian children while Sakar et al7

reported the prevalence rate of such behavior as 7.1%.Recently Sreenath et al had reported as low 0.2% byDeivasigamani.8

Bed wetting is a batting to parents but embarrassing forchildren. In this study bed wetting habits is found in 27(5.9%) school children. This disorder in children is thecause of noxious smelling of the bed. It is estimated thatup to 20.0% of six years olds and approximately 5.0%of fourteen years olds, wet their beds some timebedwetting also continues into adulthood.9

Some myth amongst parents and teacher is this kind ofhabits may communicate from parents to children. Butit is actually due to stress, anxiety, jealousy, fear orphobia which to take place in school. Only 93( 20.5%)subject takes daily bath regularly while others are taking


Figures in parenthesis are in percentages

Bahaviour n.Male Female Total

Nail biting 20 (4.4) 35 (7.7) 55 (12.1)Thumb shucking 9 (2.0) 26 (5.7) 35 (7.7)Bed wetting 6 (1.3) 21 (4.6) 27 (5.9)Food fad 4 (0.9) 3 (0.7) 7 (1.5)Temper tantrum 12 (2.6) 4 (0.88) 16 (3.5)None 200 (44.1) 114 (25.1) 314 (69.2)Total 251 (55.3) 203 (44.7) 454 (100)

Table-1: Behaviour of school children parenthesis is thepercentages

Figures in parenthesis are in percentages

Bathing habits Male Female TotalOnce a week 157 (34.6) 109 (26.2) 266 (58.6)Twice a week 33 (7.7) 41 (9) 74 (16.3)Thrice a week 8 (3.1) 13 (2.9) 21 (4.6)Regular 48 (10.6) 45 (9.9) 93 (20.5)Total 246 (54.2) 208 (45.8) 454 (100)

Table-2: Bathing habits amongst subjects (N= 454)

Figures in parenthesis are percentages

Brushing habits nMale Female Total

Once a day 187 (41.2) 146 (32.2) 333 (73.4)Twice a daya 63 (13.9) 49 (10.8) 112 (24.7)Regular 3 (0.7) 6 (1.3) 9 (2.0)Total 253 (55.7) 201(44.3) 454 (100)

Table-3: Brushing habits in school children (N=454)

189

bath very irregularly like once a week in 266 (58.6%)twice a week in 74 (16.3%) cases and thrice a week in21(4.6%) is frequently for bath (Table-2). Similarlybrushing of teeth is also erratic amongst students. Only9 (2.0%) brushes their teeth daily but in spite of this theteeth problems are not developed by this age group.

It needs regular further follow up (Table-3).

The simplest assessment is keen observation duringschool health survey for habit disorders.

Management is by treating underlying psychiatriccondition, family therapy, parental training and liaisonwith school to investigate possible reasons for refusaland negotiate re-entry.

Teachers should be taken in to confidence for trainingand initial assessment and follow up regularly. They haveto play a vital role to change their habit by the rewardand/or punishment. The counseling was provided to themduring the study period. This is due to anxiety thatchildren develop. Health education and counseling bypsychiatrist/psychiatric social worker is a need of hour.

ACKNOWLEDGMENTSThe author are thankful to Dr. S.P. Bhattarai MD and Dr. S.B.Rizyal Principal Nepal Medical College and Teaching Hospitalfor the source of inspiration to carryout this study and othercolleagues of Department of Community Medicine for theencouragement in this research.

REFERENCES

1. Tomblin JB, Zang X, Buckwalter P, Catts H. The associationof reading disability, behaviour disorders and languageimpairment among second grade children. J Child PsycholChild Psychiatr Allied Discipl 2000; 41: 473-82.

2. Hinshaw SP. Externalizing behaviour problems and academicunder achievement in childhood and adolescence: casualrelationships and underlying mechanism. Psychological Bull1992; 11: 127-55.

3. Ritter DR, Social competence and problem behaviour ofadolescent girls with learning disabilities. J LearningDisabilities 1989; 22: 460-61.

4. Kasani JH, Daniel AE, Sulzberger LA et.al. Conduct disorderadolescents from a community sample Can J Psychiatr 1987;32;56-60.

5. Harland P, Reijneveld SA, Brugman E et al. Family factorsand life events as risk factors for behavioural and emotionalproblems in children. Eur Child Adolesc Psychiatr 2002;11:176-84.

6. http.//www.patient.uk/doctor/common behavior problems inchildren. htm, common behavior problems in children/doctor/patient.

7. Sakar AB, Kapur M, Kaliaberumal VG. The prevalence andpattern of psychological disturbance in school going middlechildhood children. Natl Insti Mental Health Neuro Sci(NIMHANS) J 1996; 13:33-41.

8. Deivasignamini TR. Psychiatric morbidity in primaryschoolchildren. An epidemiological study. Indian J Psychiatr1990; 32: 235-40.

9. http:wwwispub/ journal / the internet journal of mental health,vol 1 number ISPUB- behavior problems in children andadolescents with learning disability.

PP Kafle et al

190

Assessment of kidney stone and prevalence of its chemical compositionsA Pandeya,1 R Prajapati,2 P Panta,3 and A Regmi,4

1Department of Biochemistry, 2Department of Physiology, 3Department of Community Medicine, Nepal Medical College, JorpatiKathmandu, 4Department of Biochemistry, National College for Advanced Learning , Kathmandu, Nepal

Corresponding author: Arun Pandeya, Department of Biochemistry, Nepal Medical College, Kathmandu, Nepal;e-mail: [email protected]

ABSTRACT

Kidney stone analysis is the test done on the stone which cause problems when they block the flow of urinethrough or out of the kidneys. The stones cause severe pain and are also associated with morbidity and renaldamage. There is also no clear understanding on the relative metabolic composition of renal calculi. Hence, thestudy is aimed to find out the chemical composition of it which can guide treatment and give information thatmay prevent more stones from forming. The study was carried out on the stones that had been sent to thedepartment of Biochemistry (n = 99; M = 61; F = 38; Mean age: 33.6±14.4 years) Approximately 98.9% ofstones were composed of oxalate, 95.9% of Calcium, 85.8% of phosphate, 62.6% of Urate, 46.4% of Ammoniumand very few percentages of Carbonate.Keywords: Kidney stones, renal calculi, diet, pH, urinary tract.

INTRODUCTION

Kidney Stones also called a or urolith (nephrorefers tothe kidney, urorefers to urine, and -lith means stone andthe condition is known as nephrolithiasis orurolithiasis)or renal calculi, are the extra chemicals thatare not flushed out of the system through urine and getcollected in the kidneys. These collected solidaccumulations/chemicals form crystals and harden intostones. The basis of formation of these accumulations isthe change in the normal balance of water, salts, minerals,and other substances found in urine. The main factorthat change urine balance is water, the deficiency ofwhich causes stick together of the salts, minerals, andother substances in the urine forming a stone.1 Stonescause problems when they block the flow of urinethrough or out of the kidneys. When the stones movealong the ureter, they cause severe pain and are alsoassociated with morbidity and renal damage. This studymay reveal useful information about the chemical natureof kidney stone in our general population and possibleassociation of urinary tract infection which will behelpful in adopting preventive strategies to minimizestone formation and their recurrence.

Kidney stones have multifactorial causes, but somepredisposing conditions are: Environmental factors,especially diet2,3 play an important role in expression ofthe tendency to stone formation.

Diet rich in oxalate or purines and high content ofcalcium in water can lead to excessive excretion ofcalcium, oxalate and uric acid in urine. Water deprivationcauses stasis in the tubules and concentrates the solutesthere. Absence of some dietary substances such as and

citric acid can lead to excessive amounts of oxalate andphosphate. Some drugs such as are poorly soluble andmay precipitate forming stones or become part of thestone matrix. Also some metabolic and genetic disordersmay contribute to stone formation. Beside these, pH isone of the most potent causes for stone formation asmost solutes are only soluble within a finite pH range,for example, phosphates and carbonates are insoluble atan alkaline pH. Uric acid and calcium oxalate areinsoluble at an acidic pH.4

Eighty percent of patients with nephrolithiasis formcalcium stones, most of which are composed primarilyof calcium oxalate or, less often, calcium phosphate.5,6

The other main types include uric acid, struvite(magnesium ammonium phosphate), and cystine stones.The same patient may have more than one type of stoneconcurrently (eg, calcium oxalate and uric acid). 6

A person with a family history of kidney stones may bemore likely to develop stones. Urinary tract infections,kidney disorders, certain metabolic disorders and peoplewith renal tubular acidosis are also linked to developkidney stones.

The first symptom of a kidney stone is extreme pain,which begins suddenly when a stone moves in the urinarytract and blocks the flow of urine causing a sharp,cramping pain in the back and side in the area of thekidney or in the lower abdomen and the pain may spreadto the groin. Sometimes nausea and vomiting occur.7


The study was carried out on 99 stone samples (61 males


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and 38 females), thathad been sent/received to theDepartment ofBiochemistry, NepalMedical College,Kathmandu, Nepal,

during the period of two years (2008- 2010). The age ofsubjects having stones were ranging from 5 to 72 yearswith the mean age of 33.

The stones were first examined for physicalcharacteristics. Since the most stones are mixtures andmay consists of several layers hence the stones were cutinto two halves or were powdered for analysis ofchemical compositions.8

increased metabolic waste and a predisposition of stoneformation. The other more significant cause may bebecause of the male urinary tract being more complicatedthan the female urinary tract. The study showed thehigher prevalence of stone formers ranging from 21- 40years of their age which is supported by the study ofAsplin et al.10 However, some study have stated theincreased prevalence of stones when men enter into their40s and continues to rise into their 70s. For women, theprevalence peaks in their 50s.7

The study could not find the living standard of stoneformers though stone formation depends upon thestandards of living and is strongly associated with raceor ethnicity.11 The chemicals most commonly present inkidney stones included oxalate as an organic constituentwhereas calcium and phosphate were present asinorganic constituents. Other compounds such as uricacid, ammonium and carbonate were also present as aconstituent of stones.

Kidney stones result when urine becomes tooconcentrated and substances in the urine crystallize toform stones. Besides dietary factor, the most commoncause of kidney stones is not drinking enough water.Excessive consumption of meat protein leads to a markedincrease in kidney stones because meat causes the overacidification of urine causing the increased excretion ofoxalate, calcium and uric acid, whereas the excretion ofcitrate - which provides protection against stoneformation is decreased. Overly acidic urine is the mainrisk factor for the formation of uric acid stones.

Dietary oxalate contributes to about half of the urinaryoxalate. Spinach, rhubarb, beets, chocolate, nuts, tea,wheat bran, strawberries, and soya foods are known toincrease urinary oxalate concentrations.12 Vitamin Csupplementation may increase urinary oxalate excretionand the risk of calcium oxalate crystallisation in patientswho form calcium stones13 as oxalate is the oxidizedproduct of vitamin C.

The main risk factors for calcium stones are a lowvolume of urine, increased excretion of oxalic acid andcalcium and a deficiency of citrate, which inhibitscrystallization in the urine. Also the sodium containedin common salt can increase the risk of stone formation,probably by increasing the urinary excretion of calcium.

Sex Frequency %Males 61 61.6Females 38 38.4Total 99 100

Table-1: Prevalence of stonesaccording to genders

Table-2: Prevalence of stones among different age groupsAge group Males (%) Females (%) Total (%)Up to 20 12 (80.0) 3 (20.0) 15 (15.1)21-40 28 (53.8) 24 (46.1) 52 (52.5)41-60 16 (64.0) 9 (36.0) 25 (25.2)More than 61 1 (20.0) 4 (80.0) 5 (5.0)

RESULTS

A total of 99 kidney stones were analyzed in which maledominancy is seen among stone formers i.e. 61 are males(61.6%) and only 38 are females (38.4%) which is shownin Table-1. The highest number of cases, 52.5% of thetotal case is present in age group of 21-40 years followedby 25.2% in age group of 41-60 years. The least numberof stone formers are present beyond their 60s, which isshown in Table-2. The composition of most of the stonesanalyzed were oxalate (98.9%) followed by uric acid(62.6%) as an organic constituents while as an inorganicconstituents, stones were composed of calcium (95.9%),phosphate (85.8%), ammonium (46.4%) and very fewnumber of stones were composed of carbonate (5.0%),which is shown in Table-3.

DISCUSSIONS

In present study, kidney stones were found to be morecommon in men than in women which is in accordancewith the study by Stapleton FB9 this may be because ofthe larger muscle mass of men as compared to women.Thus, the daily breakdown of the tissue results in

A Pandeya et al

Sex Frequency Organic constituents Inorganic constituentsOxalate Uric acid Calcium Phosphate Ammonium Carbonate

Males 61 61 40 58 56 29 3Females 38 37 22 37 29 17 2Total (%) 99 98 (98.9) 62 (62.6) 95 (95.9) 85 (85.8) 46 (46.4) 5 (5.0)

Table-3: Chemical composition of stones and their valid percentage

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Increased excretion of calcium results from impairedrenal tubular reabsorbtion of calcium and increased boneresorption as a result of primary hyperparathyroidism.

The abundant form of phosphate in plants is phytatewhich forms insoluble complexes with calcium in thegastrointestinal tract and reduces calcium absorption andurinary calcium excretion, that consequently couldreduce the risk of stone formation. However, this sameaction could result in increased oxalate absorption andurinary oxalate excretion, which would increase the riskof stone formation.14

Most kidney stones can pass through the urinary systemwith plenty of water—2 to 3 quarts a day—to help movethe stone along, hence a simple and most importantlifestyle change to prevent stones is to drink moreliquids—water is the best. Someone who tends to formstones should try to drink enough liquids throughout theday. The basic pathophysiology of all stones is urinarysuper saturation with respect to the stone material, andtreatment is based on decreasing or eliminating supersaturation. Normal-Calcium, Low-Sodium, and Low-Animal-Protein Diets are recommended for StonePrevention.

ACKNOWLEDGEMENTSWe are grateful to Dr. S.B. Rizyal Principal, NMC forencouraging research work. We would like to thank Mr. UmeshKarki, Technician, Department of Biochemistry, NepalMedical College, for his help during stone analysis. We wouldalso like to acknowledge everyone who were directly orindirectly involved in this study.

REFERENCES

1. Parmar MS. Kidney stones. Brit Med J 2004; 328: 1420-4.2. Goldfarb DS, Fischer ME, Keich Y, Goldberg J. A twin study

of genetic and dietary influences on nephrolithiasis: a reportfrom the Vietnam Era Twin (VET) Registry. Kidney Int’l2005; 67: 1053-61.

3. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. Aprospective study of dietary calcium and other nutrients andthe risk of symptomatic kidney stones. New Engl J Med 1993;328: 833-8.

4. Monica Rhodes. Kidney stone health center ( www.kidney.org)5. Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment

of kidney stones. New Engl J Med 1992; 327: 1141.6. Teichman, JM. Clinical practice. Acute renal colic from

ureteral calculus. New Engl J Med 2004; 350: 684.7. National Kidney and Urologic Diseases Information Clearing

House (NKUDIC). http://www.kidney.niddk.nih.gov/ NIHPublication No. 08–2495 October 2007

8. Rajagopal G, Toora BD: Renal and biliary calculi: PracticalBiochemistry (2nd ed), Ahuja publishing house, 2005; 163-6.

9. Stapleton FB. Childhood stones. Endocrinol Metabol ClinNorth Amer 2002; 31: 1001-15.

10. Asplin JR, Favus MJ, Coe FL. Nephrolithiasis. In: BrennerBM, ed. Brenner and Rector’s the kidney. 5th ed. Philadelphia:Saunders, 1996: 1893-1935

11. Stamatelou KK, Francis ME, Jones CA, Nyberg LM Jr,Curhan GC. Time trends in reported prevalence of kidneystones in the United States: 1976-1994. Kidney Int’l 2003;63: 1817-23.

12. Holmes RP, Goodman HO, Assimos DG. Contribution ofdietary oxalate to urinary oxalate excretion. Kidney Int’l2001; 59: 270-6.

13. Baxmann AC, Mendonca CD, Heilberg IP. Effect of vitaminC supplements on urinary oxalate and pH in calcium stone-forming patients. Kidney Int’l 2003; 63: 1066-71.

14. Curhan GC, Willet WC, Knight EL, Stampfer MJ. DietaryFactors and the Risk of Incident Kidney Stones in YoungerWomen, Nurses’ Health Study II. Arch Intern Med 2004;164: 885- 91.


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Hemophilic psuedotumor- is there a role of radiotherapy?Literature review and a case report

L Rijal,1 DS Neogi,2 Md T Ansari,2 SA Khan2 and CS Yadav2

Department of Orthopaedics, 1Manipal College of Medical Sciences, Pokhara, Nepal, 2All India Institute of Medical Sciences,Ansari Nagar, Delhi -110029, India

Corresponding author: Laxman Rijal, Department of Orthopaedics, Manipal College of Medical Sciences, Pokhara, Nepal;e-mail: [email protected]

ABSTRACT

We share the literature and management of an adult with moderate hemophilia a presented with a calcanealpsuedotumor and non healing ulcer by radiation therapy, factor VIII and cryoprecipitate supplement. Numerousliteratures so far have quoted the satisfactory role of radiotherapy in hemophilic psuedotumor. We found it tobe of great help as our case responded with radiotherapy, factor VIII and cryoprecipitate supplement and has asatisfactory 2 years follow up.Keywords: Hemophilia, hemophilic psuedotumor, radiotherapy, factor VIII.

INTRODUCTION

Psuedotumor of bone in patients with hemophilia is rare,but well known and serious complications. Thiscondition is seen in 1.0-2.0% of patients with eitherhemophilia A or B.1

A hemophilic psuedotumor (HP) is recognized as acollection of chronic encapsulated blood initiated in mostcase by a minor traumatic injury. This is followed byrecurrent extra-articular hemorrhage either into muscle,periosteum, or intraosseous spaces and development ofa tough surrounding fibrous capsule. Psuedotumor arecategorized as osseous and soft tissue lesions, on thebasis of anatomic location.2 The radiographic findingsof a soft tissue mass with areas of calcification andadjacent bone destruction in a patient with hemophiliais usually sufficient to make the diagnosis of apseudotumor.3 Conventional radiography, sonography,CT, and MRI each play an important role in thediagnosis, characterization and management.4-6 The massusually grows in size over months or years and presentsas features of compression of adjacent structures andincreasing destruction of bone resulting into severe painand deformity.

Treatment of this condition is difficult and requiresmultimodal approach. The treatment modality in eachpatient depends on the size of psuedotumor, site ofinvolvement and the presence of inhibitors. Varyingdegrees of success with surgical resection,7,8 radiationtherapy,9-11 combination of radiation with factorreplacement12,13 or embolization14 have been reported inliterature. Non surgical mode of treatment is being triedin form of radiotherapy alone or combined with factorVIII. We evaluated the results of previous studies and

proceed further and found good result (Table-1). Wesuggest radiotherapy can be tried in HP especially wheresurgical treatment is less helpful and disastrous.


A 23 year male, diagnosed case of moderate hemophiliaA at age 4 (factor VIII approximately 4.0%) sustained atrivial trauma and developed swelling around left ankle4 months back prior to our consultation. He was aregistered member of hemophilia society and was undertreatment from the same society. He was managed withlight compression bandage followed by factorsupplement. The acute episode of pain subsided thoughthe swelling persisted. One month later he observed thespontaneous increase in size of swelling and pain in theankle. With in few days he observed the color changearound ankle followed by skin necrosis and dischargingsinus below the lateral malleolus and medial malleolus,which progressed and later resulted into a non healingsinus. He was then referred to our center.

Case Report Nepal Med Coll J 2010; 12(3): 193-197

Fig. 1. Preradiotherapy, non healing ulcer lateral malleolus

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On examination, there was a non healing ulcer of 3x3cm just below the medial and lateral malleolus (Fig.1).Peri-malleolar swelling and change of skin color to duskyred. Slough and necrotic tissue with sero-sanguinushdischarge was seen in the bed of ulcer but there was nofrank pus. Hematological and radiological evaluationwas done immediately after admitting the patient.Hematology confirmed the diagnosis of moderate

hemophilia A and imaging with X ray (Fig. 2) and MRI(Fig. 3) suggested large lytic lesion with heterogeneousinternal contents (? Hemorrhage) in the calcaneum withcutaneous sinus on the medial and posterolateral aspect.The findings were consistent with HP with edema oftalus and fluid in the ankle and subtalar joint.

The patient was started on factor VIII at dose of 2500units every 12 hourly, supplemented with

Table-1: Outcome of patients with hemophilic pseudotumors treated with radiotherapy–review of literatureYear No of cases Age(yrs) Bones involved Treatment RT dose Outcome Author1942 1 30 Femur RT NA Resolved Muller et al26

1942 1 13 Tibia RT 16Gy Resolved Echternacht et al27

1948 1 51 Femur RT NA Noimprovement Ghormley et al28

1959 1 65 Pubis RT 23.50 Gy Stable for 2 years Horwitz et al29

1965 2 11, 13 Calcaneum and RT 15.76Gy and 16.72 Gy Resolved Chen et al30

cuboid1968 2 11, 15 Mandible and fifth RT 8Gy and 10Gy Resolved Lazarovitis et al31

metacarpal1972 3 18, 13, 57 B/L tibia. Femur F-VIII, 16Gy, 18Gy, 20Gy Resolved Brant et al32

Cyoprecipitate+RT

1975 1 2 Femur F-VIII+RT 7.5Gy Resolved Hilagartnet et al16

1984 1 12 Mandible F-IX+RT 6Gy Resolved Correra et al11

1985 1 14 Orbit Proplex+RT 7.5Gy Resolved Meyers et al33

1991 2 3, 13 Mandible and fifth F-IX+RT 6Gy, 16Gy Resolved Castaneda et al24

metacarpal1996 1 13 Tibia RT 6Gy Resolved Ozbek et al10

1998 1 15 Calcaneum F-VIII, 15Gy/10days Resolved Kashyap et al13

Cyoprecipitate+RT

1998 1 14 Ankle joint F-VIII, 14GY/7Fr Resolved Lal et al34

Cyoprecipitate+RT

2001 1 20 PNS F-VIII, 500cGy/10days Resolved Gupta et al35

Cyoprecipitate+RT

2004 1 NA Thumb F-VIII, NA Resolved Issaivanan et al12

Cyoprecipitate+RT

2005 1 30 Knee joint F-enriched 25Gy/10Fr Resolved Kapoor et al21

Cyoprecipitate+RT

2007 1 NA Hand RT 2000cGy/10Fr Stable Subhasi et al22

2008 1 6 Orbit RT 900cGy/5Fr Resolved Nongrum et al23

2009 1 23 Calcaneum F-VIII, 15Gy/7days Resolved Laxman et alCyoprecipitate +RT (current study)


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cryoprecipitate, regular dressing of the wound and lightcompression bandage was combined with externalradiotherapy for 7 days. A total of 15 Gy/7 days wasgiven and discontinued after a symptomatic relief. Post

symptom free and was bearing weight over the affectedlimb comfortable. Two months post-radiotherapy X-ray(Fig. 5) and 6 months post-radio therapy MRI (Fig. 6)scans revealed reduction in the size of the lesion withsome alteration in signal intensity due to evolution ofthe hemorrhagic products. A two years follow up issatisfactory, patient is ambulatory pain free and there isobliteration of sinus.

DISCUSSION

The diagnosis of HP is evident on the basis of clinicaljudgment, history of trauma, bleeding episodes, radioimaging and response of disease on treatment. Invasivemethods to establish diagnosis like aspiration and biopsyare not favored for the fear of complication like;uncontrolled bleeding, skin necrosis, and non healingulcers following procedures.

The mechanism of psuedotumor of bone is notunderstood well. Pathogenesis in unclear and severalcases have been suggested : a) necrosis due tocompression (bone destruction in the presence ofhemarthosis), b) subperiosteal or soft tissue hemorrhagewith necrosis and bone destruction followed by boneformation and c) intraosseal hemorrhage , followed dby cyst alterations with bone destruction and subsequenthemorrhage.15,16

The bony destruction in imaging is similar to sarcoma,tuberculosis, multiple myeloma, and metastaticconditions.17

The different classification is based upon localizationof injuries. First of them distinguishes three typesaccording to anatomical layout, secondary ossealalteration and radiological correspondence.18

Another classification distinguish between proximal HPand more frequent in adults and located in femur andpelvis and distal HP located in hands and feet, multiplemore frequent in children and with better prognosis.1

Magallon et al19 reviewed patient diagnosed withhemophilia A and B and other coagulopathies from 1965-1990. Of the 1831 patients, only 21 patients hadpsuedotumor, located mainly in the appendicularskeleton and the pelvis. Total number of patients withhemophilia A was 1108, of which only 16 patients (1.4%)had psuedotumor. Total number of patients withhemophilia B was 172, of which 4 (2.3%) hadpsuedotumor. The number of patients with othercoagulopathies was 551, of which only 1 patient (0.2%)had psuedotumor. In the series, replacement therapy andsurgery gave the good results, especially in cases thatsurgery was electively choosen.19

L Rijal et al

Fig. 2. Pre radiotherapy X-ray showing calcanealpsuedotumor.

radiotherapy follow up after 2 months showed decreasein swelling and healed sinus on the medical aspect andorganized but small persistent dry sinus on lateral sidejust below the lateral malleolus (Fig. 4). He was

Fig. 3. Pre radiotherapy MRI section showing extent oflesion.

Fig. 4. Post radiotherapy healed sinus of medial andorganized sinus of lateral malleolus

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Radiotherapy with or without factor VIII supplementhas established better results in the previous studies. Themechanism of action of radiation is postulated to be thederangement of micro vascular architecture of thepsuedotumor, resulting in increased fibroblastic activityleading to fibrosis.16,20 Secondary calcification occursin four weeks and complete healing occurs in 8-12weeks.Literature provides evidence that low dose radiation forhemophilic psuedotumor is sufficient.

Medline database search of patients with HP receivingradiotherapy with or without factor VIII replacementyielded a case report and review article of 22 cases byKapoor et al.21 Which included the study by Magallonet al also. In the subsequent years two more casesSubhasi et al22 and Nongrum et al23 were reported whowere treated by radiotherapy. The most common site ofinvolvement was the femur 5/25 (20.0%), followed bytibia 4/25 (16.0%), mandible 3/25 (12.0%), calcaneum3/25 (12.0%), orbit 2/25 (8.0%), hand 2/25 (8.0%), pubicbone 1/25 (4.0%) and ankle joint 1/25 (4.0%), Para nasalsinus involvement was seen in 1/25 (4.0%) . Fourteenof 22 (56.0%) patients only received radiotherapy while11/25 (44.0%) received radiotherapy and replacementfactors. In 23/25 (92.0%) patients, the lesion had eitherresolved or were in the process of resolving, 1 (4.0%)patient did not show any improvement, and 2/25 (8.0%)patients had stable diseases. Castaneda et al24 havereviewed 17 psuedotumor treated with radiation eitheralone or in combination with factor replacement. Theradiation dose varied between 750 cGy to 2350 cGy.Fourteen of 17 (82.0%) patients showed completeresolution, while 3/17 (18.0%) patients with factor VIIIinhibitors also responded to radiotherapy and factor VIIItherapy. Krill et al25 reviewed eight cases of hemophilichemarthosis over a period of seven years and showedthat the patient treated with radiotherapy had rapidresolution of tumor without any recurrence. Dose as lowas 600 cGy to as high as 2300 cGy with or without factorVIII replacement has shown good response.

In our case we preferred the combination therapy andthe patient was started on factor VIII at dose of 2500units every 12 hourly, supplemented withcryoprecipitate, regular dressing of the wound and lightcompression bandage was combined with externalradiotherapy for 7 days. A total of 15 Gy/7 days wasgiven and discontinued after a symptomatic relief. Twomonths clinico-radiological (X-ray) follow up revealeddramatic clinical recovery and 6 months later clinico-radiological (MRI) follow up suggested healed lesion.Now after 2 years of clinical follow up lesion has healedand he is asymptomatic even on full weight bearing.

REFERENCES

1. Ahlebrg AKM. On the natural history of hemophilicpseudotumor. J Bone Jont Surg 1975; 57A: 1133-6.

2. Resnick D. Diagnosis of bone and joint disorders, 4th ed.Philidelphia: WB saunders, 2002: 2346-73.

3. Gilbert MS. The hemophilic pseudotumor. Prog Clin BiolRes 1990; 324: 257-62.

4. Hermann G, Gilbert MS, Abdelwahab IF. Hemophilia:evaluation of musculoskeletal involvement with CT,sonography, and MR imaging. Amer J Roentgenol 1992;158: 119-23.

5. Hermann G, Yeh HC, Gilbert MS. Computed tomographyand ultrasonography of the hemophilic pseudotumor and theiruse in surgical planning. Skeletal Radiol 1986; 15: 123-8.

6. Wilson DA, Prince JR. MR imaging of hemophilicpseudotumor. Amer J Roentgenol 1998; 150: 349-50.

7. Buchowski JM, Cascio BM, Streiff MB, Frassica FJ.Resection and reconstruction of a massive femoral hemophilicpseudotumor. Clin Orthop Relat Res 2005; 430: 237-42.javascript:PopUpMenu2_Set(Menu15662330);

8. Iwata H, Oishi Y, Itoh A et al. Surgical excision of hemophilicpseudotumor of the ilium. Clin Orthop Relat Res 1992;284: 234-8.

9. Kang JO, Cho YJ, Yoo MC, Hong SE. Hemophilicpseudotumor of the ulna treated with low dose radiationtherapy: a case report. J Korean Med Sci 2000; 15: 601-3.

10. Ozbek N, Unsal M, Kara A, Gumruk F, Gurgey A. Treatmentof hemophilic pseudotumor with low-dose radiotherapy. TurkJ Pediatr 1996; 38: 91-4.


Fig. 5. Post radiotherapy X-ray showing healed lesion withsclerosis (2 months follow up).

Fig. 6. Post radiotherapy MRI section showing the healedlesion (6 months follow up MRI)

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11. Correra A, Buckley J, Roser S, Schreiber A, Syrop S.Radiotherapy of a pseudotumor in a hemophiliac with factorVIII inhibitor. Amer J Pediatr Hematol Oncol 1983; 6: 325-7.

12. Issaivanan M, Shrikande MP, Mahapatra M, Choudhry VP.Management of hemophilic pseudotumor of thumb in a child.J Pediatr Hematol Oncol 2004; 26: 128-32.

13. Kashyap R, Sarangi JN, Choudhry VP, Saxena R, MalhotraR. Pseudotumor of calcaneus; treatment with radiotherapyand replacement therapy. Amer J Hematol 1998; 57: 263-4.

14. Pisco JM, Garcia VL, Martins JM, Mascarenhas AM.Hemophilic pseudotumor treated with transcatheter arterialembolization: case report. Angiology 1990; 41: 1070-4.

15. Liu SS, White WL, Johnson PC, Gauntt C. Hemophilicpseudotumor of the spinal canal. Case report. J Neurosurg1988; 69: 624-7.

16. Hilgartner MW, Arnold WD. Hemophilic pseudotumortreated with replacement therapy and radiation. J Bone JointSurg Amer 1975; 57A: 1145-6.

17. Jensen PS, Putman CE. Hemophilic pseudotumor. Diagnosis,treatment and complications. Amer J Dis Child 1975;129: 717-9

18. Fernández de Valderrama JA, Matthews JM. The haemophilicpseudotumor or hemophilic subperiostal haematoma. J BoneJoint Surg 1965; 47: 256-65.

19. Magallon M, Monteagudo J, Altisent C et al. Hemophilicpseudotumor; multicenter experience over a 25-year period.Amer J Hematol 1994; 45: 103-8.

20. Reinhold HS. Structural changes in blood vessel. Curr TopRadiat Res Q 1974; 10: 58.

21. Kapoor R, Sastri J, Malhotra P, Kumar V, Singh P. Hemophilicpseudotumor-is there a role of radiotherapy? A case reportwith review of literature. Turk J Hematol 2006; 23: 53-8.

22. Subasi M, Dirier A, Kapukaya A, Uludag A, Karadayi B,cebesoy O. Succesful treatment of hemophilic handpseudotumors by only radiotherapy. Ann Plast Surg. 2007;59: 338-40.

23. Nongrum B, Srinivasan R, Pandian DG, Gupta A, KrishnanM. Role of radiotherapy in hemophilic pseudotumor of theorbit. Orbit. 2008; 27: 377-9.

24. Castaneda VL, Parmley RT, Bozzini M, Feldmeir JJ.Radiotherapy of pseudotumors of bone in hemophiliacs withcirculating inhibitors to factor VIII. Amer J Hematol1991; 36: 55-9.

25. Krill CE, Mauer AM. Pseudotumors of calcaneus in Christmasdisease. J Pediatr 1970; 77: 848-55.

26. Muller JH. Uber die roengentheratapie von sog.Resorptionqeshwulsten bei homophile. Stralentherapie1942; 72:281.

27. Echternacht. Pseudotumor of bone in hemophilia. Radiology1943; 41: 565-72.

28. Ghormley RK, Clegg RS. Bone and joint changes inhemophilia. J Bone Joint Surgery Amer 1948; 30A: 589-600.

29. Horwitz H, Bassen FA, Simon N. Hemophilic pseudotumorof the pelvis. Brit J Radiol 1959; 32: 51-4.

30. Chen YF. Bilateral hemophilia pseudotumor of the calcaneusand cuboid treated by radiation case report. J Bone JointSurgery Amer 1965; 47A: 517-21.

31. Lazarovits P, Greiem M. Radiotherapy of hemophilicpseudotumors. Radiology 1968; 91: 1026-7.

32. Brant EE, Jordan HH. Radiologic aspects of haemophilicpseudotumors in bone. Amer J Roentgenol Radium Ther NuclMed 1972; 115: 525-39.

33. Meyers L, Hakami N. Pseudotumor of hemophilia in the orbit:role of radiotherapy in the management. Amer J Hematol1985; 19: 99-104.

34. Lal P, Biswal BM, Thulkar S, Patel AK, Venkatesh R, JulkaPK. Radiation therapy in pseudotumor hemarthrosis.Australas Radiol 1998; 42: 344-6.

35. Gupta S, Mohapatra BB, Ghai S et al. Hemophiliapseudotumor of the paranasal sinuses: management withradiotherapy and factor replacement therapy. Hemophilia2001; 7: 595-9.

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Multiple skeletal metastases as unusual manifestations of hepatocellularcarcinoma in a noncirrhotic liver

VC Shakya,1 CS Agrawal,1 SR Pandey,2 RK Rauniyar,3 K Dhungel3 and S Adhikary1

Department of 1Surgery, 2Pathology and 3Radiology, B P Koirala Institute of Health Sciences, Dharan, Nepal

Corresponding author: Vikal Chandra Shakya, MS, Assistant Professor, Department of Surgery, B. P. Koirala Institute of HealthSciences, Dharan, Nepal; e-mail: [email protected]

ABSTRACT

Hepatocellular carcinoma is the most frequent primary malignant tumor of the liver. Bony metastases ofhepatocellular carcinoma are usually rare, in which most common sites involved are vertebra and pelvis. Stillrarer are metastases to the chest wall and skull. We report a case of a 45-year old man with unusual metastasesof hepatocellular carcinoma to skull, sternum and ribs. These combinations of metastases have rarely beenreported in literature.Keywords: Sternal metastases; skull metastasis; osteolytic lesions; aflatoxin B; cirrhosis.

Hepatocellular carcinoma (HCC) is the most frequentprimary malignant tumor of the liver.1 It is usually seenin the sixth and seventh decades of life in the westernworld, whereas in Asia and Africa, it usually occurs inthe fourth decade of life.2 It is found more commonly inthe males.2 A definite association between HCC andcirrhosis has been found, with chronic hepatitis B viralinfection being described as the most common cause.3-5

It has been found to metastasize commonly to the lungs,regional lymph nodes, kidneys, bones and adrenals.4-9

Multiple bony metastases to the skull and the chest wallhave rarely been reported before. This report presents amiddle aged male with unusual metastasis of HCC whichmanifested initially as multiple swellings on the midsternum and anterolateral aspect of the chest wall andthe skull.

CASE REPORT

A 45 year old male presented to our hospital withcomplaints of swelling in the central and rightanterolateral region of the chest and the right side of theskull, loss of weight, loss of appetite and generalweakness of 3 months duration. There was no history ofpain over the swellings, jaundice, fever, night sweats.He was nonalcoholic. His physical examination revealeda 3 × 2 cm fixed hard swelling in the right side of theskull and two hard swellings of varying sizes at the midsternum and right anterolateral region of the chest. Therewas no pallor, icterus or ascites. On abdominalexamination, he had mild nontender hepatomegaly. Hewas anemic with hemoglobin of 8.5 mg/dL. Total anddirect bilirubin and liver enzymes were within normallimits. Viral marker profile was not reactive for bothHBsAg and HCV. Other causes of liver disease wereeliminated by assessment of antinuclear, anti-

mitochondrial, anti-smooth-muscle and anti-microsomalantibodies. Iron metabolism study was also normal.

The radiograph of the skull demonstrated an osteolyticlesion involving the right frontal bone. Computerizedtomography (CT) of the skull revealed a destructivelesion with erosion of the right frontal bone (Fig. 1). CTscan of the thorax revealed soft tissue lesions on thecentral and right anterolateral aspect of the chest witherosion of the sternum and right 5th and 6th ribsrespectively (Fig. 2). Abdominal CT scan detected a4.6cm x 4.1cm well circumscribed heterogenous lesionin the right lobe of the liver (Fig. 3). The rest of the liverparenchyma was normal. There was nolymphadenopathy on thoracic, abdominal or pelvic scan.Microscopic examination of the biopsy specimen fromthe skull and chest wall lesions revealed pleomorphictumor cells with eosinophilic cytoplasm, prominentnucleoli and mitosis arranged in trabecular and solid


Fig.1. Axial CT scan of the skull (bone window) showing alytic lesion in the right frontal bone.

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pattern, suggestive of metastatic hepatocellularcarcinoma (Fig. 4). Cytological examination of a fineneedle aspirate taken from the lesion in the liver wasconsistent with the diagnosis of hepatocellular carcinoma(Fig. 5). The serum alpha-feto protein (AFP) level ofthe patient was elevated (33,566 ng/mL; normal 0-13.6ng/ml). The patient was discharged on palliativetreatment. After 2 months of diagnosis and 5 months ofappearance of the symptoms, he is still continuing withfollow-up. No other swellings have appeared, he hasweight loss and increase in size of the describedswellings.

DISCUSSION

Bony metastases from HCC are now being reported morecommonly than ever before. They are seen in 3.0-10.0%of HCC patients.10-15 The bones most commonly involvedare the vertebra, pelvis, ribs and skull.16 Isolatedmetastases to the ribs, sternum and the skull have beenreported.17-24 Multiple metastases to the chest wall andthe skull in the same patient have rarely been reportedin the literature.

The bony lesion due to metastatic HCC in this case wasosteolytic and discrete. However, multiple osteolytic

lesions simulating multiple myeloma can be due tometastatic HCC.25

The etiology of HCC is still unknown in this patient.There were no clinical or laboratory parameters orradiological features of chronic liver disease. HCC hasbeen found usually to develop on a background ofcirrhosis (cirrhomimetic) but can also originate in normalor nincirrhotic hepatic parenchyma (non-cirrhomimetic).26 In fact, in South African blackpopulation, 37.0% of primary HCC occurs in patientswithout cirrhosis.26 One cause that can be attributed isaflatoxin B produced by aspergillus species which growsas a contaminant in stored cereals and grains in a hothumid climate. A close correlation between the degreeof fungal contamination and frequency of HCC has beenreported in tropical areas like sub-Saharan Africa andSouth East Asia, though the frequency is less wellestablished in our part of the world, due to lack ofstudies.27,28 We believe such a relation might exist in ourpatient. Studies using histochemical detection ofaflatoxin B in patients with HCC will be needed furtherto establish the causative role in our region also.

VC Shakya et al

Fig.5. Cytological examination from the lesion in the livershows malignant hepatocytes, suggestive of hepatocellular

carcinoma (X 400 Papanicolaou stain)

Fig.2. CT scan of the thorax showing lytic lesionsinvolving the sternum and right 5th rib adjacent to the

costochondral junction with soft tissue extension.

Fig. 3. CT scan of the abdomen showing a well definedheterogeneous mass lesion in the right lobe of the liver.

Fig.4. Photomicrograph of the biopsy taken from the chestwall and skull lesions shows malignant hepatocytes,

consistent with metastatic hepatocellular carcinoma. (X 400Haematoxylin and Eosin stain)

200

Metastatic HCC without an unknown primary is adefinite subset that poses a great challenge in thediagnosis.17,18,24 The cause has been postulated to beectopic liver carcinogenesis and hepatoidadenocarcinoma found to occur in the stomach, ovary,uterus, renal pelvis, bladder, pancreas and lungs.24,29-31

In our case, there was little difficulty in the detection ofthe primary which was confirmed by the fine needleaspiration cytology.

We conclude hereby that metastasis of HCC should beincluded in the differential diagnosis of bony swellingseven in the absence of chronic liver disease.

REFERENCES

1. Anthony P. Hepatocellular carcinoma: an overview.Histopathol 2001; 39: 109-18.

2. Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer:worldwide incidence and trends. Gastroenterol 2004; 127: s5-16.

3. Befeler A, Bisceglie AM. Hepatocellular carcinoma: diagnosisand treatment. Gastroenterol 2002; 122: 1609-19.

4. Katyal S, Oliver JH, Peterson MS, Ferris JV, Carr BS, BaronRL. Extrahepatic metastasis of hepatocellular carcinoma.Radiol 2000; 216: 698-703.

5. Tang ZY. Hepatocellular carcinoma: cause, treatment andmetastasis. World J Gastroenterol 2001; 7: 445-54.

6. Pawarode A, Voravud N, Sriuranpong V, Kullavanijaya P,Patt YZ. Natural history of untreated primary hepatocellularcarcinoma: a retrospective study of 157 patients. Amer J ClinOncol 1998; 2: 386-91.

7. The Liver Cancer Study Group of Japan. Primary liver cancerin Japan: Clinicopathologic features and results of surgicaltreatment. Ann Surg 1990; 211: 277- 87.

8. Okusaka T, Okada S, Ishii H et al. Prognosis of hepatocellularcarcinoma patients with extrahepatic metastases.Hepatogastroenterol 1997; 44: 251-7.

9. Kummar S, Shafi NQ. Metastatic hepatocellular carcinoma.Clin Oncol (R Coll Radiol) 2003; 15: 288-94.

10. Si MS, Amersi F, Golish SR et al. Prevalence of metastasesin hepatocellular carcinoma: risk factors and impact onsurvival. Amer Surg 2003; 69: 879-85.

11. Doval DC, Rama Rao C, Acharya R, Reddy BKM, BapsyPP. Hepatocellular carcinoma metastatic to bones. Indian JCancer 1995; 32: 31-5.

12. Edmondson HA, Stenier PE. Primary carcinoma of liver: astudy of 100 cases among 48,900 necropsies. Cancer 1954;7: 462-503.

13. Okuda K. Clinical aspects of hepatocellular carcinoma:analysis of 134 cases. In Okuda K, Peters RL (editors):Hepatocellular carcinoma. New York: John Wiley & Sons1976; 387-436.

14. Liaw CC, Kim Thean NG, Chen TJ, Liaw YF. Hepatocellularcarcinoma presenting as bone metastasis. Cancer 1989; 64:1753-7.

15. Okazaki N, Yoshino M, Yoshida T, Hirohashi S, Kishi K,Shimosato Y. Bone metastasis in hepatocellular carcinoma.Cancer 1985; 55: 1991-4.

16. Fukutomi M, Yokota M, Chuman H, et al. Increased incidenceof bone metastases in hepatocellular carcinoma. Eur JGastroenterol Hepatol 2001; 13: 1083-8.

17. Horita K, Okazaki Y, Haraguchi A, Natsuaki M, Itoh T. Acase of solitary sternal metastasis from unknown primaryhepatocellular carcinoma. Nippon Kyobu Geka Gakkai Zasshi1996; 44: 959-64.

18. Hofmann HS, Spillner J, Hammer M, Diez C. A solitary chestwall metastasis from unknown primary hepatocellularcarcinoma. Eur J Gastroenterol Hepatol 2003; 15: 557-9.

19. Melichar B, Voboril Z, Toupkova M, Dvorak J. Hepatocellularcarcinoma presenting with bone metastasis. J Exp Clin CancerRes 2002; 21: 433-6.

20. Shuffett WL, Richardson JD, McGee EM, Jewell WR.Hepatoma metastatic to rib. J Amer Med Assoc 1971; 215: 120.

21. Soto S, Artaza T, Gomez R et al. Rib metastasis revealinghepatocellular carcinoma. Scand J Gastroenterol 2000;35: 333-6.

22. González-Flores V, Alcántara-Vázquez A, Hernández-González M, Pérez-Espinoza J, Ortiz-Hidalgo C. Sternalmetastases as first presentation of hepatocellular carcinoma:a case report. Rev Med Hosp Gen Mex 2007; 70: 184-8.

23. Hsieh CT, Sun JM, Tsai WC, Tsai TH, Chiang YH, Liu MY.Skull metastasis from hepatocellular carcinoma. ActaNeurochir 2007; 149: 185-90.

24. Hyun YS, Choi HS, Bae JH et al. Chest wall metastasis fromunknown primary site of hepatocellular carcinoma. World JGastroenterol 2006; 12: 2139-42.

25. Doval DC, Bhatia K, Vaid AK, Prabhash K, Jena A, HazarikaD. Bone metastases from primary hepatocellular carcinomasimulating multiple myeloma. Hepatobiliary Pancreat DisInt’l 2005; 4: 308-10.

26. Cushieri A. Disorders of the liver. In Cushieri A, Steele RJC,Moossa AR (editors): Essential surgical practice: highersurgical training in general surgery (4th ed). New York;Arnold 2002: 353.

27. Yu MC, Yuan JM. Environmental factors and risk forhepatocellular carcinoma. Gastroenterol 2004; 127: s72-8.

28. Wogan GM. Dietary risk factors for primary hepatocellularcarcinoma. Cancer Detect Prev 1989; 14: 209.

29. Arakawa M, Kimura Y, Sakata K, Kubo Y, Fukushima T,Okuda K. Propensity of ectopic liver to hepatocarcinogenesis:case reports and a review of the literature. Hepatol 1999;29: 57-61.

30. Asselah T, Condat B, Cazals-Hatem D et al. Ectopichepatocellular carcinoma arising in the left chest wall: a long-term follow-up. Eur J Gastroenterol Hepatol 2001; 13: 873-5.

31. Kishimoto T, Nagai Y, Kato K, Ozaki D, Ishikura H. Hepatoidadenocarcinoma: a new clinicopathological entity and thehypotheses on carcinogenesis. Med Electron Microsc 2000;33: 57-63.


201

Adrenal gland teratoma in a 40-year-old womanMK Shrestha and S Lalchan

Manipal College of Medical Sciences, P.O.Box 341, Phulbari, Pokhara, Nepal

Corresponding author: M. K. Shrestha, MBBS, MD Manipal College of Medical Sciences,P.O.Box 341, Phulbari, Pokhara-33701, Nepal

ABSTRACT

Teratoma is a germ-cell tumor that commonly affects the gonads. Extragondal teratoma is a rare entity. Teratomain the region of adrenal gland is a rare and uncommon retroperitoneal tumor; only few cases have been reported.This case report describes such a tumor in a 40-year-old-woman who presented with multiple vague complaints.Ultrasonography of the abdomen showed a mixed echogenic mass with areas of calcification in right supra-renal region and a lymph nodal mass in the right renal hilar region. Computed tomography showed a masscontaining fat, calcification and soft tissue component in right supra-renal region indenting the superior pole ofkidney. Intraoperatively a supra-renal tumor was found within in a pseudocapsule that covered most of thetumor with a part of duodenum fixed to the mass.

CASE REPORT

A 40- year-old female had been visiting different hospitalwith series of multiple vague complaints like chest pain,headache, excessive fear, dizziness for past 3-4 years.Batteries of tests were carried out such as bloodinvestigations, thyroid function test, renal function testetc. which all yielded negative results. She was thenreferred to psychiatry department where she wasdiagnosed to have somatoform disorder and wasreceiving treatment accordingly. Finally after fewmonths she landed up in our department forultrasonography as she had presented with pain over leftlumbar region and left hypochondrium.

An ultrasound scan showed a mixed echogenic masswith hypoechoic areas and calcifications in right suprarenal region with retrocaval extension. The tumor mildlydisplaced the kidney inferiorly. A lymphnodal mass wasalso seen at right renal hilum. CT revealed a rightsuprarenal mass measuring approximately 9x8x5 cm.The mass was mainly fat containing with soft tissue andcalcific components. Post- contrast studies showed noparticular pattern of enhancement (Fig. 1-2).

In view of the possibility of malignant nature of the tumorsuch as liposarcoma, the patient underwent laparotomy

and abdominal exploration. Intraoperatively supra renalmass was found with retrocaval, retro-aortic extensionand upto the crux of diaphragm. The mass was also seenfixed to a part of the duodenum.

Histological examination revealed a mature teratoma.Mature adipose tissue, smooth muscle bundles, andglands with mucin production were also noted.Dystrophic Calcification and ossification were seenfocally. The adrenal gland was present at the peripheryof the tumor. The patient’s condition was stable afterthe operation and was discharged uneventfully.

DISCUSSION

Teratomas are congenital tumors thought to arise frompluripotent embryonal cells.1 Teratomas can occur inalmost any region of the body, but are most commonlyfound in paraxial and midline locations.2 Reports ofteratomas in the region of the adrenal gland are rare inliterature.3 Lipomatous tumors of the adrenal gland arealso not commonly seen. They include lipoma,


Fig. 1. CT axial section at level of adrenal gland showingheterogenously enhancing mass lesion containing fat,

calcification and soft tissue component

Fig. 2. Cut section of the specimen showing cystic spacescontaining pultaceous and mucoid material with areas ofcartilage and bony tissue. Periphery shows compressed

adrenal tissue

202

to occur after that age.13 Incidental finding of teratomaoccurring in the region of adrenal gland in a 77-year-old man has also been reported.14 Thus teratoma shouldbe considered in differential diagnosis of adrenallipomatous tumours – in all age groups.

REFERENCE

1. Ashley DJ. Origin of teratomas. Cancer 1973; 32: 390-4.2. Azizkhan RG, Caty MG. Teratomas in childhood. Curr Opin

Pediatr 1996; 8: 287-92.3. Lam KY, Lo CY. Teratoma in the region of adrenal gland: A

unique entity masquerading as lipomatous adrenal tumor.Surgery 1999; 126: 90-4.

4. Kenney PJ, Wagner BJ, Rao P, Heffess CS. Myelolipoma:CT and pathological features. Radiol 1998; 208: 87-95.

5. Behan M, Martin EC, Muecke EC et al. Myelolipoma of theadrenal: two cases with ultrasound and CT findings. Amer JRoentgenol 1977; 129: 993-6.

6. Lam KY, Chan AC, Ng IO. Giant adrenal lipoma: a report oftwo cases and review of literature. Scand J Urol Nephrol 1997;31: 89-90.

7. Buttner A. Lipoma of the adrenal gland. Pathol Int’l 1999;49: 1001-9.

8. Bruneton JN, Diard F, Drouillard JP et al. Primaryretroperitoneal teratoma in adults: presentation of two casesand review of literature. Radiol 1980; 134: 613-6.

9. Goyal M, Sharma R, Sawhney P et al. The unusual imagingappearance of primary retroperitoneal teratoma: report of acase. Surg Today 1997; 27: 282-4.

10. Polsky MS, Shackelford GD, Weber CH Jr et al.Retroperitoneal teratoma. Urol 1976; 8: 618-21.

11. Davidson AJ, Hartman DS, Goldman SM. Mature teratomaof retroperitoneum: radiologic, pathologic, and clinicalcorrelation. Radiol 1989; 172: 421-5.

12. Lam KY, Lo CY. Adrenal lipomatous tumors: a 30 yearclinoco-pathological experience at a single institution. J ClinPathol 2001; 54: 707-12.

13. Bedri S, Erfanian K, Schwaitzberg S et al. Mature cysticteratoma involving adrenal gland. Endocr Pathol 2002; 13:59-64.

14. Hui JPK, Luk WH, Siu CW et al. Teratoma in the region ofadrenal gland in a 77-year-old man. J Hong Kong Coll Radiol2004; 7: 206-09.

myelolipoma, teratoma, angiomyolipoma, andliposarcoma.4,5 These patients are asymptomatic andoften present with non-specific complaints.6,7

Retroperitoneal teratomas are more common duringchildhood than at other time, and they are rare entity inadults.8,9 Malignant change is also more commonly foundin adults than in children (26.0% vs 10.0%).8,10

Abdominal radiograph may demonstrate mass with fatwith either calcification or bone. Similarly,ultrasonography shows uncomplicated fluid andcalcification. Fat is not reliably distinguished from othersoft tissue components by ultrasonography. CTdemonstrates a heterogenous mass containing well-circumscribed fluid component of variable volume,adipose tissue or sebum in form of fat-fluid level, andcalcification.11 MRI may demonstrate the characteristicsignal of fat (hyperintensity) and water (hypointensity)in T1-weighted images.

The presence of calcification is more common interatomas than in other lipomatous tumours.Calcification in myelolipomas is not as common as interatomas.12 The presence of calcification in adrenallipomas is also an uncommon finding. CT images ofangiomyolipoma demonstrate mainly fatty componentand tiny soft tissue densities interspersed within thetumor. Calcifications are also rare in angiomyolipomas.

Liposarcoma is most common adult form of soft tissuesarcoma and may present on CT imaging with cystic,muscle, or fat density.

The 40-year-old lady in our case had an incidentalfinding of retroperitoneal lipomatous tumor in whichthe possibility of malignancy, such as liposarcoma, couldnot be excluded. Surgical resection was thus performedand histopathological report confirmed it as teratoma.Primary retroperitoneal teratoma is unusual in patientsabove the age of 30 years; only 10.0% have been reported


PATRONS

Dr. Sachey Kumar PahariKathmandu, Nepal (1998)

Prof. Anjani Kumar SharmaKathmandu, Nepal (1998)

Dr. Ram Ratna UapdhayayKathmandu, Nepal (1998)

Er. Deepak BhattaraiKathmandu, Nepal (1998)

Prof. Pramila PradhanKathmandu, Nepal (1998)

Prof. Naimeswor Prosad SinhaDehli, India (1998)

Er. Ram Badan ShresthaKathmandu, Nepal (1999)

Dr. Dharma Raj ShresthaKathmandu, Nepal (1999)

Dr. Rumiko Okamoto (Shrestha)Tokyo, Japan (2001)

Dr. Yasuo SugataTokyo, Japan (2001)

Mr. Babu Ram PokharelKathmandu, Nepal (2002)

Mr. Jiro AsahiTamada Gakuen, Kobe, Japan (2002)

Dr. Mikio SekitaTokiwa Hospital, Miki, Japan (2002)

Mr. Terumasa KourogiTokiwa Hospital, Miki, Japan (2002)

Prof. Sadako YufuneTokiwa College, Kobe, Japan (2002)

Dr. Kazuo OnoTokiwa College, Kobe, Japan (2002)

Mr. Punya Prasad LohaniKathmandu, Nepal (2004)

Nepal Medical College JournalVol. 12 No. 3 September 2010 Regd. No. 88/054-55

ADVISORY BOARD

Dr. Sachey Kumar PahariProf. Anjani Kumar Sharma

Prof. Hemang DixitDr. Shekhar Babu Rizyal

Prof. Sanjib Dhungel

EDITORIAL BOARD

(Publication Sub-committee of NMC-IRC)

CHIEF EDITORProf. Shiba Kumar Rai, PhD(Med), DMSc

(M Vidya Bhushan Ka, Kha & Ga all 3 classes)

EDITORS (MEMBERS)Dr. Tapas Pramanik, MSc, PhDDr. Sunil Shrestha, MBBS, MSDr. Aparna Rizyal, MBBS, MDDr. Heera Tuladhar, MBBS, MD

INTERNATIONAL EDITORSProf. Shoji Uga

Kobe University Graduate School of Health Sciences,Kobe, Japan

Emr. Prof. Ramesh Chandler MahajanPGIMER, Chandigarh, India

Dr. Kazuo OnoKobe Tokiwa University, Kobe, Japan

Prof. Daniel ColleyCenter for Tropical & Emerging Global Diseases,

University of Georgia, USA

Dr. Indah TantularTDRC, Airlangga University, Surabaya, Indonesia

Dr. Yo HtutDept of Med Research, Ministry of Health, Myanmar

Dr. Smarn TesanaFaculty of Medicine, Khon Kaen University, Thailand

Prof. Geok Lin KhorChief Editor, Malaysian J Nutrition, Malaysia

SUPPORT STAFFMr. Rameshwor Chalise

Website: www.nmcth.edu and/or www.nmcj.org.npE-mail: [email protected] and/or [email protected]

FOUNDER CHIEF EDITORDr. Hari Krishna Banskota, MBBS, MD

(1998-2002)

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Vol. 12 No. 3 September 2010 Regd. No. 88/054-55

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CHIEF EDITOR: Prof. Shiba Kumar Rai, PhD(Med), DMSc, (M Vidya Bhushan Ka, Kha & Ga all 3 classes)EDITORS: Dr. Tapas Pramanik, MSc, PhD, Dr. Sunil Shrestha, MS, Dr. Aparna Rizyal, MD, & Dr. Heera Tuladhar, MD

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Original Articles1. Study of relationship between facial index and gestational age in normal newborns

A Satija, S Kaushal, PVV Gopichand and U Chhabra 133-136

2. Two new variants of G6PD deficiencies in SingaporeM Hamada, T Shirakawa, Lai Poh-San, K Nishiyama, S Uga and M Matsuo 137-141

3. Dermatoglyphics of fingers and palm in klinefelter’s syndromeBR Sontakke, SK Ghosh and AK Pal 142-144

4. The composition and quantitative analysis of urinary calculi in patients with renal calculiS Jawalekar, VT Surve and AK Bhutey 145-148

5. Long term effects of Monosodium glutamate on spermatogenesis following neonatal exposurein Albino mice – a histological studyRS Das and SK Ghosh 149-153

6. Immediate effect of a slow pace breathing exercise Bhramari pranayama on blood pressure andheart rateT Pramanik, B Pudasaini and R Prajapati 154-157

7. Serum lipid and lipoprotein profile abnormality in predicting the risk of coronary artery diseasein non-diabetic patients attending NMCTH, BirgunjM Adak and JN Shivapuri 158-164

8. Changing tuberculosis trends in Nepal in the period 2001-2008L Shrestha, KK Jha and P Malla 165-170

9. A study of depression and anxiety in cancer patientsP Thapa, N Rawal and Bista Y 171-175

10. Changing routes of hysterectomy : a cross sectional and comparative studyNS Shrestha, R Saha and C Karki 176-179

11. An evaluation of pulmonary parameters in two groups of subjects during Yoga practiceQR Ahmed, SK Sau and SK Kar 180-182

12. Age at menarche of subpopulation of Nepalese girlsL Sunuwar, CG Saha, Anupa KC and K Upadhyay Dhungel 183-186

13. Common behaviour problems amongst primary school children in slum dwelling area ofKathmandu valleyPP Kafle, L Vaidya, PP Panta , MR Chhetri and SK Mehrotra, 187-189

14. Assessment of kidney stone and prevalence of its chemical compositionsA Pandeya, R Prajapati, P Panta, and A Regmi, 190-192

Case Report15. Hemophilic psuedotumor- is there a role of radiotherapy? Literature review and a case report

L Rijal, DS Neogi, Md T Ansari, SA Khan and CS Yadav 193-197

16. Multiple skeletal metastases as unusual manifestations of hepatocellular carcinoma in anoncirrhotic liverVC Shakya, CS Agrawal, SR Pandey, RK Rauniyar, K Dhungel and S Adhikary 198-200

17. Adrenal gland teratoma in a 40-year-old womanMK Shrestha and S Lalchan 201-202

FOR FUTHER INFORMATIONS: Attarkhel, Jorpati VDC-7, Kathmandu, P.O. Box: 13344, NEPALPhone: 4911008, Fax: 00977-1-4912118, Email: [email protected] Website: www.nmcth.edu

immediate effect of a slow pace breathing exercise bhramari

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