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Tumor necrosis factor α in the pathophysiology of necrotizing enterocolitis
594
CORRESPONDENCE
GASTROENTEROLOGY
environmental factors] will all significantly influence the magnitude and in some instances the direction of the responses observed. Thus, the experimental model is crucial. It is not surprising then that different investigators report different immunologic results. In addition, when dealing with alcohol studies, the dosing is absolutely critical in that low doses appear to be stimulatory while high doses are markedly suppressive within 3 days of initiation of treatment (2). Drs. Heij and Marquet do not state in their letter how many of these modulating parameters were identical in their studies and ours. However, despite whatever differences may have existed in the experimental model, in the first 3 months they observed a depression in the number of splenic lymphocytes, a depressed response to PHA (presumably blast transformation), and depressed humoral antibody production in response to sheep red blood cells. These changes are consistent with our observed suppressed host response in vivo to mycobacterial infections and PHA skin test responses. The primary concern of Heij and Marquet is that continued long-term alcoholism after 3 months is associated with a diminution and disappearance of a detectable alcohol immunosuppression, which they interpret as an “adaptation to the effects of alcohol.” Unfortunately, they do not detail whether the loss of alcohol immunosuppression was caused by deterioration in control animal responses or by improvement in the alcoholic animals toward control levels. We have previously studied age effects and reported a physiological decline in immune responses related to aging (3). This response was seen in both control and alcoholic rats, and hence was not merely an adaptive effect to alcohol. We take further issue with Drs. Heij and Marquet regarding the appropriateness of 3 weeks of alcohol treatment in rats. Humans have a life expectancy of about 70 years. In rats, the expectancy is about 30 months, a 28-fold difference in longevity. Therefore, in rats, 3 weeks of alcoholism is equivalent to 1.75 years in humans, 3 months in rats is equivalent to 7 years in humans, and 24 months in rats is equivalent to 56 years in humans. Because age blunts the immune response, the chronic alcohol effect becomes less detectible in senescence. The major importance of these findings is the need to control carefully for age in the rat alcohol model and emphasize younger rats on a relatively short period. C. L. MENDENHALL, M.D., Ph.D. C. J. GROSSMAN, Ph.D. G. A. ROSELLE, M.D. Department of Veterans Affairs Medical Center Hepatic Research Lab Cincinnati, Ohio Grossman CJ. Gonadal steroids and immune response. Science 1985;227:257-261. Dehne HE, Mendenhall CL, Roselle GA, Grossman CJ. Cell mediated immune responses associated with short term alcohol intake: time course and dose dependency. Alcoholism Clin Exp Res 1989;13:201-205. Roselle GA, Mendenhall CL, Grossman CJ. Age dependent alterations of host immune response in the ethanol-fed rat. J Clin Lab Immunol1989;29:99-103.
Tumor Necrosis Pathophysiology
Factor a- in the of Necrotizing Enterocolitis
Dear Sir: Recent studies implicate tumor necrosis factor a in the pathophysiology of necrotizing enterocolitis (1,2). This same cytokine contributes to the morbidity of acute bacterial meningitis (3). In the latter
Vol. 101, No. 2
circumstance, treatment with steroids (dexamethasone) ameliorates the adverse effects of tumor necrosis factor by inhibiting message transcription and translation (4). Might the salutary effects of steroids in preventing necrotizing enterocolitis as described by Israel et al (5) be in some measure attributable to this alternative mechanism? ARTHUR G. WEINBERG, M.D.
Professor of Pathology and Pediatrics University of Texas Health Science Center Dallas, Texas 75235 1. Caplan MS, Sun X, Hsueh W, Hageman Jr, Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 1990;116:960-964. induced by tumor necrosis 2. Sun X, Hsueh W. Bowel necrosis factor in rats is mediated by platelet-activating factor. J Clin Invest 1988;81:1328-1331, GH Jr. 3. Mustata MM, Ramilo 0, Hansen EJ, Beutler B, McCracken Modulation of inflammation and cachectin (TNFo) activity in relation to treatment of experimental Haemophilus influenzae meningitis. JInfect Dis 1989;160:818-825. 4. Beutler B, Krochin N, Milsark IW, Leudke C, Cerami A. Control of cachectin [tumor necrosis factor) synthesis: mechanism of endotoxin resistance. Science 1986;232:977-980, EJ, Schiffrin EJ, Carter EA, Freiberg E, Walker WA. 5. Israel Prevention of necrotizing enterocolitis in the rat with prenatal cortisone. Gastroenterology 1990;99:1333-1338,
Fasting and Postprandial Gallbladder Volumes
Residual
Dear Sir: In agreement with previous studies (1,2), Festi et al. recently reported in “Gastroenterology” that fasting and postprandial residual gallbladder volumes are increased for gallstone patients as compared with normal subjects (3). Treatment with ursodeoxycholic acid in 38 patients led to even higher fasting gallbladder volumes, as previously reported by our group (4). However, the finding of Festi et al. that ursodeoxycholic acid treatment leads to further deterioration of postprandial gallbladder emptying and further increased postprandial residual volumes is in contradistinction to a previous publication from the same authors (5). In that study on 25 gallstone patients, Festi et al. found significantly increased fasting gallbladder volumes but unchanged postprandial residual volumes during ursodeoxycholic acid treatment (Table 1) and concluded that “ursodeoxycholic acid does not induce slower and less complete gallbladder emptying,” which is in agreement with results from our group (4). In addition, the suggestion of Festi et al. (3) that ursodeoxycholic acid treatment might decrease postprandial cholecystokinin release
Table
Before 1 mo
I.
Gallbladder Dynamics Before and During Ursodeoxycholic Acid Therapy in 25 Gallstone Patients Basal volume
Residual volume
(mL)
(mL)
Emptying (%)
AUC (mL/I 80 min)
22.3 -c 11.0
10.5 c 7.4
53.9
+ 16.0
5.2 + 2.9
25.8 k 12.2*
10.3 2 6.6
59.8 + 14.3
6.4 k 5.4
3mo
26.8 f
6mo
23.5 2 7.6
8.2*
9.6 2 5.3
58.6 2 11.4
5.2 2 2.4
9.8 -c 6.0
56.3 + 10.4
5.4 5 3.1
NOTE. Results are means ? SD. “P < 0.05 vs. before (paired Wilcoxon Data from Festi et al. (5).
test).
CORRESPONDENCE
GASTROENTEROLOGY
environmental factors] will all significantly influence the magnitude and in some instances the direction of the responses observed. Thus, the experimental model is crucial. It is not surprising then that different investigators report different immunologic results. In addition, when dealing with alcohol studies, the dosing is absolutely critical in that low doses appear to be stimulatory while high doses are markedly suppressive within 3 days of initiation of treatment (2). Drs. Heij and Marquet do not state in their letter how many of these modulating parameters were identical in their studies and ours. However, despite whatever differences may have existed in the experimental model, in the first 3 months they observed a depression in the number of splenic lymphocytes, a depressed response to PHA (presumably blast transformation), and depressed humoral antibody production in response to sheep red blood cells. These changes are consistent with our observed suppressed host response in vivo to mycobacterial infections and PHA skin test responses. The primary concern of Heij and Marquet is that continued long-term alcoholism after 3 months is associated with a diminution and disappearance of a detectable alcohol immunosuppression, which they interpret as an “adaptation to the effects of alcohol.” Unfortunately, they do not detail whether the loss of alcohol immunosuppression was caused by deterioration in control animal responses or by improvement in the alcoholic animals toward control levels. We have previously studied age effects and reported a physiological decline in immune responses related to aging (3). This response was seen in both control and alcoholic rats, and hence was not merely an adaptive effect to alcohol. We take further issue with Drs. Heij and Marquet regarding the appropriateness of 3 weeks of alcohol treatment in rats. Humans have a life expectancy of about 70 years. In rats, the expectancy is about 30 months, a 28-fold difference in longevity. Therefore, in rats, 3 weeks of alcoholism is equivalent to 1.75 years in humans, 3 months in rats is equivalent to 7 years in humans, and 24 months in rats is equivalent to 56 years in humans. Because age blunts the immune response, the chronic alcohol effect becomes less detectible in senescence. The major importance of these findings is the need to control carefully for age in the rat alcohol model and emphasize younger rats on a relatively short period. C. L. MENDENHALL, M.D., Ph.D. C. J. GROSSMAN, Ph.D. G. A. ROSELLE, M.D. Department of Veterans Affairs Medical Center Hepatic Research Lab Cincinnati, Ohio Grossman CJ. Gonadal steroids and immune response. Science 1985;227:257-261. Dehne HE, Mendenhall CL, Roselle GA, Grossman CJ. Cell mediated immune responses associated with short term alcohol intake: time course and dose dependency. Alcoholism Clin Exp Res 1989;13:201-205. Roselle GA, Mendenhall CL, Grossman CJ. Age dependent alterations of host immune response in the ethanol-fed rat. J Clin Lab Immunol1989;29:99-103.
Tumor Necrosis Pathophysiology
Factor a- in the of Necrotizing Enterocolitis
Dear Sir: Recent studies implicate tumor necrosis factor a in the pathophysiology of necrotizing enterocolitis (1,2). This same cytokine contributes to the morbidity of acute bacterial meningitis (3). In the latter
Vol. 101, No. 2
circumstance, treatment with steroids (dexamethasone) ameliorates the adverse effects of tumor necrosis factor by inhibiting message transcription and translation (4). Might the salutary effects of steroids in preventing necrotizing enterocolitis as described by Israel et al (5) be in some measure attributable to this alternative mechanism? ARTHUR G. WEINBERG, M.D.
Professor of Pathology and Pediatrics University of Texas Health Science Center Dallas, Texas 75235 1. Caplan MS, Sun X, Hsueh W, Hageman Jr, Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 1990;116:960-964. induced by tumor necrosis 2. Sun X, Hsueh W. Bowel necrosis factor in rats is mediated by platelet-activating factor. J Clin Invest 1988;81:1328-1331, GH Jr. 3. Mustata MM, Ramilo 0, Hansen EJ, Beutler B, McCracken Modulation of inflammation and cachectin (TNFo) activity in relation to treatment of experimental Haemophilus influenzae meningitis. JInfect Dis 1989;160:818-825. 4. Beutler B, Krochin N, Milsark IW, Leudke C, Cerami A. Control of cachectin [tumor necrosis factor) synthesis: mechanism of endotoxin resistance. Science 1986;232:977-980, EJ, Schiffrin EJ, Carter EA, Freiberg E, Walker WA. 5. Israel Prevention of necrotizing enterocolitis in the rat with prenatal cortisone. Gastroenterology 1990;99:1333-1338,
Fasting and Postprandial Gallbladder Volumes
Residual
Dear Sir: In agreement with previous studies (1,2), Festi et al. recently reported in “Gastroenterology” that fasting and postprandial residual gallbladder volumes are increased for gallstone patients as compared with normal subjects (3). Treatment with ursodeoxycholic acid in 38 patients led to even higher fasting gallbladder volumes, as previously reported by our group (4). However, the finding of Festi et al. that ursodeoxycholic acid treatment leads to further deterioration of postprandial gallbladder emptying and further increased postprandial residual volumes is in contradistinction to a previous publication from the same authors (5). In that study on 25 gallstone patients, Festi et al. found significantly increased fasting gallbladder volumes but unchanged postprandial residual volumes during ursodeoxycholic acid treatment (Table 1) and concluded that “ursodeoxycholic acid does not induce slower and less complete gallbladder emptying,” which is in agreement with results from our group (4). In addition, the suggestion of Festi et al. (3) that ursodeoxycholic acid treatment might decrease postprandial cholecystokinin release
Table
Before 1 mo
I.
Gallbladder Dynamics Before and During Ursodeoxycholic Acid Therapy in 25 Gallstone Patients Basal volume
Residual volume
(mL)
(mL)
Emptying (%)
AUC (mL/I 80 min)
22.3 -c 11.0
10.5 c 7.4
53.9
+ 16.0
5.2 + 2.9
25.8 k 12.2*
10.3 2 6.6
59.8 + 14.3
6.4 k 5.4
3mo
26.8 f
6mo
23.5 2 7.6
8.2*
9.6 2 5.3
58.6 2 11.4
5.2 2 2.4
9.8 -c 6.0
56.3 + 10.4
5.4 5 3.1
NOTE. Results are means ? SD. “P < 0.05 vs. before (paired Wilcoxon Data from Festi et al. (5).
test).