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Cytological alteration in the rat stomach postburn Harris, Curtis Norman 1972

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ci  CYTOLOGICAL ALTERATION IN THE RAT STOMACH POSTBURN by CURTIS NORMAK HARRIS B. Sc., Oregon State University M.D., Loma Linda University  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in the Department of SURGERY  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA September,  1972  In p r e s e n t i n g t h i s t h e s i s  in p a r t i a l  f u l f i l m e n t o f the r e q u i r e m e n t s  an advanced degree at the U n i v e r s i t y o f B r i t i s h Columbia, the L i b r a r y  s h a l l make i t  freely available  for  I agree  thesis  f o r s c h o l a r l y purposes may be g r a n t e d by the Head o f my Department representatives.  It  of this thesis for financial written  Department  Columbia  or  publication  g a i n s h a l l not be a l l o w e d w i t h o u t my  of  The U n i v e r s i t y o f B r i t i s h Vancouver 8, Canada  Date  i s u n d e r s t o o d t h a t copying o r  permission.  that  r e f e r e n c e and s t u d y .  I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying o f t h i s  by h i s  for  i  ABSTRACT Gastric mucosal erosions were induced i n the glandular stomach of rats by scalding.  The incorporation of Thymidine-  methyl-^-H into desoxyribonucleic acid was used to determine changes i n gastric epithelial c e l l proliferating a b i l i t y .  Total  desoxyribonucleic acid per milligram of gastric tissue was also determined.  Sampling was done at twenty-four hours, seven days,  and fifteen days postburn. Eighty-nine point two percent of rats with a standard 26,5 t 2% scald burn had developed gastric mucosal erosions by twenty-four hours postburn.  Seventeen point eight percent of  burned rats had erosions by seven days and the incidence rose to hS,h% by fifteen days postburn.  Ten point three percent of control  rats i n a l l sampling periods developed erosions. The total desoxyribonucleic acid i n the gastric samples did not change significantly i n any treatment period nor was i t changed by treatment.  Uptake of thymldine-methyl^-H was depressed twenty-  four hours postburn and renewed so through seven days postburn. The results at the fifteen day sampling were inconclusive. By light microscope, the gastric surface epithelium was l i f t e d from the lamina propria and at times there was complete denudation of this c e l l layer.  ii The rat is a satisfactory animal model for gross study of mucosal erosions to at least fifteen day postburn.  Because of  eschar cannibalization inducing variable secretory status, the rat model was not suitable for thymidine uptake studies past seven days postburn.  iii  TABLE OF CONTENTS Page ABSTRACT  i  LIST OF TABLES  v  LIST OF FIGURES OR ILLUSTRATIONS CHAPTER I  vi  - Introduction  1  CHAPTER I I - Methods of Experimentation:  3  animals  •  3  preparation f o r treatment  3  method of treatment  3  gastric lesions  6  histology  11  n u c l e i c a c i d studies  11  CHAPTER I I I - R e s u l t s :  13  incidence of g a s t r i c erosions  13  h i s t o l o g y , gross and microscopic  13  gross specimens  13  microscopic specimens  18 •a  i n c o r p o r a t i o n o f Thymidine-methyl -H ....  22  t o t a l c e l l u l a r desoxyribonucleic a c i d ...  27  CHAPTER IV - Summary and Conclusions:  32  Summary  32  Conclusions  3k  iv Page BIBLIOGRAPHY  35  APPENDIX  30  V  LIST OF TABLES Page Table I  -  Frequency Distribution of Number of Erosions per Stomach During Treatment Periods  19 3  Table II  -  Thymidine-methyl -H uptake counts and total cellular Desoxyribonucleic Acid for twenty-four hour treated and  Table III -  untreated rats Thymidine-methyl^-H uptake counts and  39  total cellular Desoxyribonucleic Acid for seven day treated and untreated rats •  hO  3 Table IV -  Thymidine-methyl -H uptake counts and total cellular Desoxyribonucleic Acid for fifteen day treated and untreated rats  Ul  vi  LIST OF ILLUSTRATIONS Page Figure I:  Clipped and epilated Wistar rat prior to treatment  Figure II:  5  White Wistar rat twenty-four hours postburn  8  Figure III:  White Wistar rat seven days postburn  8  Figure IV:  White Wistar rat fifteen days postburn . . .  Figure V:  Percentage of animals developing gastric lesions during treatment periods  Figure VI:  17  Multiple mucosal erosions i n stomach of rat twenty-four hours postburn  Figure VIII:  15  Opened stomach from uriburned rat with no mucosal lesions  Figure VII:  10  17  Uriburned rat skin after clipping and epilation (from original magnification xl20)  Figure IX:  ,  21  Full thickness injury to rat skin after burn treatment at 88°C for twenty seconds (from original magnification xl20)  Figure X:  21  Intact surface epithelium of gastric mucosa from unburned rat (from original magnification xl20)  2h  vii Page Figure XI:  Extensive sub epithelial vacuolization of gastric mucosa from a burned rat (from original magnification xl20)  Figure XII:  2h  Absence of surface epithelium of gastric mucosa from a burned rat (from original magnification xl20)  Figure XIII:  /  26  Specific activity of Desoxyribonucleic Acid following injection of Thyroidine3  methyl- H i n the glandular stomach i n uriburned rats and rats 2h hours, 7 days and 15 days postburn Figure XIV:  29  Total Desoxyribonucleic Acid content of tissue samples from glandular stomachs of uriburned and burned rats after 2h hours, 7 day and 15 day treatment periods  31  1  INTRODUCTION I n 1842 Thomas C u r l i n g (9) presented t e n cases of duodenal u l c e r a t i o n associated w i t h burns before the Medical-Surgical Society of London.  Since that time the l e s i o n which bears h i s  name has been expanded to include g a s t r i c u l c e r a t i o n s as w e l l as duodenal.  Other traumatic and disease s t a t e s have also been  associated w i t h g a s t r o i n t e s t i n a l u l c e r a t i o n s ; e.g. i n t r a c r a n i a l l e s i o n (10), trauma (18), coronary o c c l u s i o n (30), c o r pulmonale (15), and these are now c o l l e c t i v e l y termed "STRESS ULCER." I n 1965 S e v i t t (UU) reported an incidence of twenty-two percent g a s t r i c and duodenal u l c e r a t i o n s i n two-hundred and ninety-one p a t i e n t s autopsied f o l l o w i n g burns.  I n 1970, P r u i t t  and h i s group from Brooke Army H o s p i t a l reported an o v e r a l l incidence of 11.7  percent "Curling's U l c e r " w i t h approximately  19  percent o f those dying of a cause d i r e c t l y r e l a t e d to the u l c e r or an operation thereon ( 3 8 ) .  This complication i s a s i g n i f i c a n t  problem i n burns as w e l l as other forms of trauma. The cause o r causes of these u l c e r a t i o n s i s not known. Following Davenport's experiments i n 196Ii (13, 12) there has been an increased impetus to determine what defect occurs i n the g a s t r i c mucosal b a r r i e r during episodes of s t r e s s . Increasing evidence i n dicates that there may not be one cause and each d i f f e r e n t type of s t r e s s may have a d i f f e r e n t e l l i c i t i n g mechanism.  2 The mucous layer (35, 37, 2, 25, 8), gastric acid (36, 29, 31, 4), gastric epithelial c e l l (29, 49, 40, 26) and electrolyte flux (11, 13, 12, 23, 31) have a l l been subjected to study c l i n i c ally and experimentally.  In the experimental animal the stress has  been most often induced by restraint (29, 31) with the duration therefore being short. This experiment was undertaken to study changes i n the proliferation of the gastric epithelial c e l l following burn induced stress i n the r a t .  As the c l i n i c a l burn i s a chronic illness, the  duration of the study was extended beyond the usual short 2U-U8 hour treatment.  3  METHODS OF EXPERIMENTATION Animals White male and female Wistar rats weighing from 175 grams to 275 grams were randomly paired.  These pairs were then divided  into three treatment groups of twenty-eight pairs.  The animals  were placed i n individual cages and given a standard laboratory diet and water ad libitum.  Food was withdrawn eighteen hours  prior to treatment or sacrifice.  Water was allowed ad libitum  at a l l times. Preparation for Treatment The rats were anesthetized with Sodium Pentobarbital, 5 milligrams per kilogram intraperitoneally.  The backs were clipped  with standard animal clippers from behind the ears to the t a i l and well down on the flanks.  "MEET", a commercially available depila-  tory was next applied to the clipped area, allowed to remain a few minutes and then washed off leaving the skin bare of hair.  The  animals were then dried with a towel and are shown for treatment in Figure I .  Those rats randomly selected to be controls received  20 m i l l i l i t r e s of physiological saline intraperitoneally and were returned to their cages. Method of Treatment A standard 26.5 + 2 percent f u l l thickness burn was produced  Figure I:  Clipped and Epilated Wistar rat prior to treatment.  6 on the back of the rat by scalding.  This was accomplished by using  the weight immersion principle and a machine originally developed by Bailey, Lewis and Blocker (l) and extensively modified by Courtemanche (6).  The temperature of the water was maintained at  88° Centigrade and the duration of treatment was twenty seconds. Following burning the rats were dried, given 20 m i l l i l i t r e s of physiological saline intraperitoneally and returned to their cages. The pairs of rats were sacrificed at twenty-four hours, seven days and fifteen days postburn, and the appearance of the burned rats is shown i n Figure II on page 8, Figure III on page 8, and Figure IV on page 10 respectively. were i n each treatment-day group.  Twenty-eight pairs of rats  Following an eighteen hour fast,  except for water, they were anesthetized with ether and the abdomen opened.  The esophagus and pylorus were ligated with black s i l k and  the stomach excised and placed immediately i n ice cold 0.9 Normal saline.  The animals were then killed by incising the aorta or  femoral artery and allowing exsanguination.  Animals dying before  sacrifice were discarded. Gastric Lesions The excised stomachs were opened along the greater curvature and the glandular stomach examined with a 10 x power dissecting microscope for mucosal erosions.  The presence or absence of lesions  was recorded and the significance determined by using the Pearson Chi Square test with continuity correction (17).  7  Figure II:  Figure III:  White Wistar rat twentyfour hours postburn.  White Wistar rat seven days postburn.  6  9  Figure IV: White Wistar rat fifteen days postburn.  10  11 Statistics were computed to test treatment effect, batch and day effects using the University of British Columbia Computing Centre's ANOVAR system (17). Histology Sections of the glandular stomach were removed for histological examination by hematoxylin and eosin staining (ll;). Nucleic Acid Studies The incorporation of Thymidine-methyl^-H (TdR^-H, 20 c/m Swartz-Mann) into the deoxyribonucleic acid of the gastric epithelial c e l l was measured i n control and burned rats.  At the completion of  the treatment period each rat was injected intraperitoneally with 2^0 pc of TdR -H per kilogram of body weight.  Treatment was contin-  ued for ninety minutes before sacrifice. F u l l thickness specimens of glandular stomach of approximately equal size were obtained using a #3 cork borer.  Each specimen  was weighed and immediately placed i n ice-cold 0.01 molar Tris Buffer for total DNA analysis (29) or Hyamine hydroxide for TdR^-H uptake analysis (39).  An attempt was made not to include erosions i n the  specimens. Total DNA was extracted by a method described by Ludwig and Lipkin (29).  Two f u l l thickness specimen cores were homogenized  with a Teflon pestle i n 3 m i l l i l i t r e s of ice-cold 0.01 molar Tris Buffer.  The acid insoluble material was precipitated by adding  12 one m i l l i l i t r e of cold 2N perchloric acid and the precipitate then washed twice with two m i l l i l i t r e s of 75, 95 and 100 percent alcohol, a one to one mixture of alcohol-ether and ether. sample was allowed to dry overnight.  The remaining  The next day these samples  were hydrolyzed i n one m i l l i l i t r e of 0.5 N perchloric acid. The diphenylamine procedure of Seibert (Ii3, 5) was used for the f i n a l coloriraetric deteimination of total DNA.  One volume of  the hydrolized material was added to two volumes of diphenylamine solution and the mixture heated at 100° C for ten minutes.  The  absorption curve was read on a Perkin-Elmer spectrophotometer at 650 ji and 595/i (5). Standardization was with highly polymerized calf thymus deoxyribonucleic acid (Sigma Chemical Company).  Results  were recorded as micrograms of DNA per milligram of tissue. One f u l l thickness core of glandular stomach was placed i n a scintillation v i a l with one m i l l i l i t r e of Hyamine Hydroxide and digested at 50° C for I48 hours (hi, 39 , 50). After digestion the sample was decolorized with six drops of 30 percent hydrogen peroxide (19) and acidified to pH 5 with four to six drops of glacial acetic acid (20). Fifteen m i l l i l i t r e s of Aquasol Scintillation fluid (New England Nuclear) were then added, mixed, and the solution counted for ten minutes in the Picker Liquid Scintillation Counter. Results were recorded as counts per minute per milligram of tissue. Final figures were subjected to two way analysis-of-variance for count rate and for total DNA.  13  RESULTS Incidence of Gastric Erosions In Figure V, frequency of erosions of the glandular stomach of burned and uriburned rats is shown.  Lesions developed i n 10.7  (3 of 28) per cent of uriburned rats i n each of the three treatment periods.  Eighty-nine point two percent (25 of 28) of burned rats  had developed erosions by twenty-four hours post treatment.  By day  seven the number of burned rats with erosions had declined to 17.8 percent (5 of 28).  The frequency of lesions then increased again  i n the treatment group at day fifteen to U6.U percent (13 of 28). The significance of these results as analyzed by the Pearson Chi Square test is also shown i n Figure V. At one day pJD.OOOl and at fifteen days peO.008.  The frequency of gastric ulcerations i n  burned versus nonburned rats was not of statistical significance at seven days post treatment (p=0.703).  The maximum number of erosions  occurred i n the burned animals during the f i r s t twenty-four hour treatment period. Histology, Gross and Microscopic Gross Specimens In Figure VI, page 17, are shown the gross characteristics of the opened stomach i n an untreated r a t .  The pink glandular  Figure V: Percentage of animals developing gastric lesions during treatment periods.  15  16  Figure VI: Opened stomach from uriburned rat with no mucosal lesions.  Figure VII:  Multiple mucosal erosions in stomach of rat twenty-four hours postburn.  17  18 portion of the stomach is clearly without lesions.  In contrast i s  the stomach from a burned rat shown i n Figure VII, page 17.  Multiple  erosions of various sizes are present on the glandular portion of this specimen.  Some treated animals seemed more l i k e l y to develop  multiple ulcerations than others, given the same amount of stress. Multiple lesions were more frequent overall than single lesions as shown i n Table I .  The frequency of multiple lesions did not increase  with duration of treatment i n this experiment i n contrast to the increasing numbers of lesions with duration of treatment shown by Ludwig and Idpkin (29) i n their study of restraint stressed guinea pigs.  Multiple erosions were not seen i n the untreated animals.  Microscopic Specimens An hematoxylin and eosin preparation of normal rat skin after clipping and epilation with NEET i s shown i n Figure VIII, page 21. The epidermis and dermis have been minimally changed by the chemical treatment.  Figure IX, page 21, is a representative section after  burn treatment demonstrating the f u l l thickness injury imposed by the burn.  Disruption of the epidermis with coagulation necrosis of  the underlying dermis and subcutaneous tissue are readily discernible. The glandular stomach of the rat i s normally covered with columnar epithelial cells with mucous neck cells, parietal and zymogenic cells lining the gastric pits as shown i n Figure X, page 2U.  Changes following treatment were mainly confined to the surface  19  TABLE I Frequency Distribution of Number of Erosions per Stomach During Treatment Periods.  Number of Stomachs  Day 1  Day 7  Day 15  1  2  2  5  2-3  9  1  5  4+  lit  2  3  #92  60  61.9  Percent of total stomachs with erosions i n which lesions were multiple.  20  Figure VIII:  Figure IX:  Uriburned rat skin after clipping and epilation (from original magnification xl20).  Full thickness injury to rat skin after burn treatment at 88°C for twenty seconds (from original magnification x 120).  21  22 epithelium and sub-epithelial areas.  Many histological sections  were similar to Figure XI, page 2h, i n showing large patches of surface epithelium lifted from the lamina propria.  More marked  damage i s seen i n some other areas (Figure XII, page 26), where there was complete destruction of the surface epithelium.  Both of  these histological changes were more frequent twenty-four hours postburn than later treatment periods.  Non-burned rats rarely  exhibited subepithelial vacuolization and never denudation. Incorporation of Thymidine-methyl-^H (TdR^-H) The surface epithelium of the rat stomach is a renewing c e l l population (35) and does so at a relatively constant rate i n the unstressed animal (3U). The rate of regeneration i s not significantly changed by the age of the animal (21) but the secretory rate is a major factor.  Hunt demonstrated a marked increase i n the gastric  epithelial c e l l mitotic activity i n the secreting rat over the fasting animal (22), thus, the importance of food withdrawal eighteen hours before treatment or sacrifice i n this study. Each c e l l nucleus contains desoxyribonucleic acid (DNA). This consists of two long polynucleotide chains made up of pyrimidine bases, phosphoric acid and pentose sugars.  With c e l l duplication the  specific pyrimidine base Thymine is taken up from the circulating pool and i t is at this point TdR^-H can be inserted as a label (U2) to estimate changes i n c e l l populations.  A close relationship exists  23  Figure X: Intact surface epithelium of gastric mucosa from uriburned rat ( from original magnification x 120).  Figure XI: Extensive sub epithelial vacuolization of gastric mucosa from a burned rat (from original magnification xl20).  2k  25  Figure XII: Absence of surface epithelium of gastric mucosa from a burned rat (from original magnification xl20).  26  27  between the uptake of this labeled Thymidine and mitosis (35). species has a constant amount of DNA per nucleus (1*8).  Each  This serves  as a baseline which i n conjunction with TdR^-H uptake by the gastric epithelial c e l l allows an accurate estimation of changes i n the proliferation a b i l i t y of these c e l l s . The specific activity of TdR^-H is shown in Figure XIII. There i s a significant decrease i n uptake i n burned rats (p 4.0.0001) at twenty-four hours post treatment.  This reduction i n uptake  continued through day seven (p= . 0 0 1 5 ) .  On the fifteenth postburn  day there was an apparent increase in uptake i n the treated group over the untreated animals.  However, i n subjecting this to analysis  of variance this increase was not s t a t i s t i c a l l y significant (p=0.6591). Total Cellular Desoxyribonucleic Acid In Figure XIV, page 31, are shown the relationships of total DNA i n the noriburned and burned rats during the fifteen day treatment period.  The range was 13 to 56 micrograms of DNA per milligram  of glandular stomach with a mean of 38.579 micrograms per milligram i n untreated animals and a mean of I4O.U36 micrograms per milligram i n the treated ones.  Computing the s t a t i s t i c a l significance by the  analysis of variance resulted i n p=0.0903 at 2k hours, p=O.7010 at seven days and p=O.U376 at fifteen days.  28  Figure XIII:  Specific activity of Desoxyribonucleic Acid following injection of Thymidine-methyl-^H i n the glandular stomach i n unburned rats and rats 2h hours, 7 days and 15 days postburn.  (THYMIDINE H-3 UPTAKE) DAYS POSTBURN  30  Figure XIV:  Total Desoxyribonucleic Acid content of tissue samples from glandular stomachs of uriburned and burned rats after 24 hours, 7 day. and 15 day treatment periods.  31  iiiiimii = MEAN CONTROL BURN  llllllll  Infliu run mi  P=.0903  P=. 4376  P=. 7010  I 7 DAYS POSTBURN  15  32  SUMMARY AND CONCLUSIONS Summary: This experiment has demonstrated the feasibility of using the standard burned rat to study burn induced gastric changes to fifteen days postburn.  Gross and microscopic changes are easily  followed. The incidence of mucosal lesions during the f i r s t twenty-four hours (89.2$) was similar to other reports (31, Ul, 1°, 3). A b i phasic distribution of erosions with peaks at one day and fifteen days postburn was observed.  This resembles the results reported by  Sevitt (UU) i n his autopsy study of burned humans.  The mechanism  of this is not known but he suggested that the i n i t i a l lesions were as a direct result of the injury with subsequent healing, and then reulceration.  Daily sampling of burned animals throughout the  treatment period would be helpful i n confirming this distribution. The incidence of mucosal lesions i n control animals was higher (10.7$) than most studies.  The anesthesia, clipping, epilat-  ing and washing of these animals apparently produced a significant amount of stress. Variability of the rats i n response to stress was also observed. Genetic factors (U5) and environmental factors such as housing and diet (2U, U6) have been implicated.  A l l rats i n this study were of  33 similar breeding and received identical pre-stress treatment thus minimizing any of these differences. Morphological study demonstrated formation of a subepithelial space.  This progressive l i f t i n g of the surface epithelium resulted  i n denudation and probably subsequent digestion of the lamina propria by intra luminal enzymes.  These are similar to observations reported  by Chiu, McArdle and Brown i n a study of low flow rates and intestinal epithelium (7).  In their experiment the rats were fasted twenty-  four hours after scalding.  This fluid deprivation was found to i n -  crease the incidence of gastric erosion.  They postulated that this  increase was secondary to a low flow state.  In this study rats were  allowed ad libitum water before and after burning.  In addition,  intraperitoneal saline was given immediately after treatment. A high incidence of mucosal erosions s t i l l occurred.  This would seem  to refute Chiu's postulation but may mean only that a low flow state occurred i n spite of the fluid intake, the fluid intake was inadequate for the degree of trauma or other unknown mechanisms were i n force. The incorporation of thymidine into desoxyribonucleic acid was depressed at twenty-four hours postburn and remained low through seven days postburn. By fifteen days postburn an overall increase i n thymidine uptake appeared to be present i n the burned animals. This situation can probably be attributed to the variable secretory rate i n this group and which is reflected i n the wide range of counts (Appendix A ) .  It was not possible to maintain a fasting state i n  34 some of these animals as is required.for basal mitotic activity (22) because many rats would cannibalize their own eschar. secretory rate and thus thymidine uptake.  This increases  No satisfactory method to  prevent this was devised other than to substitute a non-carnivorous animal such as the guinea pig. Total DNA content remained unchanged and i n association with the uptake studies indicates reduction i n thymidine incorporation into DNA and thus decreased DNA synthesis and c e l l proliferation to day seven postburn.  Continued depression of proliferation l i k e l y  occurs but i n view of the above cited difficulties remains unproven. Conclusions: 1. The rat i s a satisfactory animal for gross and microscopic study of gastric erosions up to fifteen days postburn. 2.  Gastric mucosal c e l l proliferation is significantly  depressed one day to seven days postburn as measured by thymidine's  methyl-^-II.  Eschar cannibalization is the probable cause of variable  results at fifteen days postburn. 3.  The total DNA content of the stomach mucosa is not sig-  nificantly changed within fifteen days postburn despite the severe injury and resulting debility. 4.  The exact etiology of mucosal erosions i n burns remains  unknown but the decreased ability of the surface epithelium to renew adequately seems to be a contributing factor.  35  BIBLIOGRAPHY 1.  B a i l e y , B.N., S.R. Lewis and T.G. Blocken, "Standardization of Experimental Burns i n the Laboratory Rat", Texas Reports on Biology & Medicine, 20: 20, 1962.  2.  B a l l i n g e r , W.F. & L. Wise, " G a s t r i c Mucousj Quantitative and Q u a l i t a t i v e Studies i n Humans & Dogs", B r i t i s h Journal of Surgery, V o l . 56: 701, 1969.  3.  Brodie, D.A., "Experimental Peptic U l c e r " , V o l . 55: 125, 1968.  Gastroenterology,  4. Brodie, D.A., " E f f e c t o f R e s t r a i n t Stress on G a s t r i c A c i d i t y i n the Rat", American Journal of Physiology, V o l . 202: 812, 1962. 5.  Chargoff, E., & S.N. Davidson, ed., L. Dische, "Color Reactions of Nucleic A c i d Components", The Nucleic Acids, V o l . I , p. 285, 1955.  6.  Courtemanche, A.D., "A C o n t r o l l e d Burning Apparatus Based on the Weight Immersion P r i n c i p l e " , B r i t i s h Journal o f P l a s t i c Surgery, V o l . 19: 23, 1966.  7.  Chiu, C.J., A.H. McArdle, & R.A. Brown, " I n t e s t i n a l Mucosal Lesion i n Low Flow S t a t e s : I . A Morphological, Hemodynamic and Metabolic Reappraisal", Archives of Surgery, V o l . 101: 478, 1970.  8.  Chiu, C.J., A.H. McArdle, & R.A. Brown, " G a s t r i c Mucosal Changes Following Burns i n Rats", Archives of Surgery, V o l . 103: 147, 1971.  9.  C u r l i n g , T.B., "On U l c e r a t i o n o f the Duodenum i n Cases o f Burn", Medico-Chirurgical Transactions, V o l . 25: 260-281, 1842.  10.  Cushing, H., "Peptic Ulcers and the I n t e r b r a i n " , Surgery, Gynecology & O b s t e t r i c s , V o l . 55: 1-33, 1932.  11.  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Vendrely, "La Teneur du noyau cellulaire en acide de'soxribonucle'ique a. travers les organes, les individus et les especes animales," Experientia, V o l . 4:  434, 1948.  Young, Kim S., Robert Kerr, Martin Lipkin, "Cell Proliferation During Development of Stress Erosions i n Mouse Stomach," Nature, 215: 1180, 1967. "Protosol the Superior Solubilizer," Bulletin, Boston, 1972.  New England Nuclear  APPENDIX  39 TABLE II Thymidine-methyl^-H uptake counts and total cellular Desoxyribonucleic Acid for twenty-four hour treated and untreated rats. TdR -H Scintillation Counts/Milligrams Tissue/Minute 3  1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.  14. 15.  16. 17. 18. 19. 20. 21. 22.  23. 24. 25. 26. 27. 28.  Control Rat  Burned Rat  19.240 18.639 25.116 21.165 15.854  12.735 9.94 13.292 15.529 9.48 12.491 165.623 183.015  17.500  186.790 182.117 201.962 187.077 160.425 171.035 215.700 193.954 169.251 164.159 63.960  61.242  114.562  54.661 57.710 80.823 42.892 84.560 77.394 121.310 48.367 54.327  159.355 109.434  151.671  I88.338 209.102 146.967 148.147 153.762 43.627 35.257 37.162 34.600 31.682 30.407 11.761 19.406 17.375 11.511 29.050 18.208  Total Micrograms DMA/Milligram Tissue Control Rat .324 .295 .370 .281 .401 .436 .310 .232 .387 .330 .309 .330 .364 .368 .282 .290 .410 .422 .456 .278 .365 .328 .377 .337 .320 .336 .373 .326  Burned Rat .274 .310 .390 .408 .522 .428 .326 .322 .342 .308 .366 .460 .317 .360 .406 .324 .420 .406 .543 .409 .356 .276 .409 .260 .327 .322 .420 .290  Uo TABLE III Thymidine-raethyl^-H uptake counts and total cellular Desoxyribonucleic Acid for seven days treated and untreated rats TcbV-H Scintillation Counts/Milligrams Tissue/Minute Control Rat 1. 2. 3. U. 5. 6. 7. 8. 9. 10. 11. 12. 13. lU. 15. 16. 17. 18. 19. 20. 21. 22. 23. 2U. 25. 26. 27. 28.  205.907 170.249 197.106 25U.672 13U.905 256.275 217.9U5 213.464 221.522 276.131 236.823 183.3U7 155.022 216.861 172.22U 170.665 251.455 145.328 71.068 U8.733 30.U65 36.313 6U.156 44.785 UU.860 52.347 83.788 103.061  Burned Rat 192.939 145.372 136.891 135.936 141.183 155.150 277.377 25U.U75 231.1U7 216.909 227.287 180.0U7 152.777 151.06U 158.746 191.603 179.528 129.098 28.692 27.598 28.800 28.989 28.787 36.143 15.066 23.93U 28.U50 36.802  Total Micrograms DMA/Milligram Tissue Control Rat .Uoi .3lU .362 .418 .333 .263 .283 .328 .300 .326 .361 .340 .304 .408 .272 .297 .267 .246 .155 .174 .281 .266 .089 .101 .276 .276 .327 .326  Burned Rat .321 .271 .255 .U08 .353 .342 .382 .336 .318 .333 .330 .317 .297 .362 .340 .240 .311 .277 .159 .228 .241 .294 .155 .106 .318 .336 .325 .276  TABLE IV Thymidine-methyl^-H uptake counts and total cellular Desoxyribonucleic Acid for fifteen days treated and untreated rats. TdR -H Scintillation Counts/Milligrams Tissue/Minute 3  Control Rat 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.  230.211 323.682 319.530 240.009 289.970 242.601 198.861 169.715 38.853 29.849 49.106 72.028 218.547 220.316 194.487 229.695 228.085 257.952 292.984 215.026 202.045 188.808 146.461 222.342 203.453 191.102 311.8^0 224.290  Burned Rat 183.297 229.735 463.117 910.968 535.234 111.414 22.177 5U.586 83.944 48.413 238.548 152.576 196.343 152.576 217.950 184.940 223.780 200.077 267.961 145.151 150.852 154.588 163.226 202.090 267.494 240.852  Total Micrograms DNA/MLlligram Tissue Control Rat  Burned Rat  .339 .291 .29U .230 .295 .380 .285 .261 .316 .297 .352 .319  .331 .259 .287 .296 .363 .244 .224 .215 .338 .390 .418 .323 .204 .338 .340 .338 .350 .440 .473 .419 .471 .450 .450 .383 .438 .385 .400 .257  .336 .372 .371 .371 .345 .385  .366  .347 .370 .362 .373 .391 .476 .476 .342 .320  

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