Role of oxygen free radicals in the etiology of pouchitis

Transient mucosal ischemia may cause oxygen-derived free radical production by xanthine oxidase, precipitating pouchitis after ileal pouch-anal anastomosis. Our aim, therefore, was to determine the effect of allopurinol, a xanthine oxidase inhibitor, in patients with acute and chronic pouchitis. Acute pouchitis was characterized clinically by sporadic episodes of increased frequency and decreased viscosity of stools, hematochezia, fever, malaise, and pelvic pain, which resolved promptly with treatment. Chronic pouchitis patients required continuous treatment to remain asymptomatic and invariably developed the signs and symptoms of pouchitis within one week following cessation of therapy. Eight patients with acute pouchitis were treated with allopurinol (300 mg p.o. b.i.d.) during the episode. Fourteen patients with chronic pouchitis had their standard antibiotic therapy discontinued while still asymptomatic; they were then given allopurinol (300 mg p.o. b.i.d.) for 28 days. Acute pouchitis resolved promptly in four of eight patients. Seven of the 14 patients with chronic pouchitis responded completely with no recurrence of symptoms during treatment. Allopurinol either terminated an episode of acute pouchitis or prevented pouchitis from recurring in 50 percent of patients. These data support a role for mucosal ischemia and oxygen free radical production in the etiology of pouchitis.     

Mechanism-Specific Antiarrhythmic Effects of the Potassium Channel Activator Levcromakalim Against Repolarization-Dependent Tachycardias

Mechanism-Specific Action of Levcromakalim. Introduction: The hypothesis that levcromakalim. a potassium channel (I_K-ATP.) activator with antihypertensive properties, has a mechanism-specific antiarrhythmic action against repolarization-dependent ventricular tachycardias (VTs) was tested in dogs. Methods and Results: A low dose of leveromakalim (0.01 mg/kg) was selected, which decreased blood pressure by 25% but had almost no electrophysiologic effect on AV nodal or ventricular conduction or effective refractory period. In dogs with chronic AV block, the antiarrhythmic action of this dose of levcromakalim was evaluated in three models of abnormal impulse formation: (I) dsotalol (2 mg/kg) induced torsades de pointes VT, initiated by early afterdepolarizations (EADs). (2) sustained ouabain-induced VTs, which are dependent on delayed after depolarizations (DADs), and (3) VT occurring 24 hours after left anterior descending coronary artery occlusion, which are likely based on abnormal automaticity. Levcromakalim abolished d-sotalol induced U waves, ventricular ectopic beats, and self-terminating bouts of torsades de pointes. Induction of torsades de pointes by pacing was also completely prevented. The cycle length of the idioventricular rhythm, which was lengthened after d-sotalol from 1490 ± 515 to 1700 ± 610 msec (P < 0.05), remained similar after levcromakalim (1655 ± 580 msec). The QT(U) duration, which was increased after d-sotalol from 410 ± 55 to 550 ± 40 msec (P < 0.05), normalized to 405 ± 70 msec (P < 0.05). Lcvcromakulim did not suppress but rather enhanced ouabain-induced VT by decreasing the cycle length slightly from 315 ± 35 to 290 ± 35 msec (P < 0.05). Pretreatment with a beta Mocker prevented this acceleration in rate. Finally, levcromakalim had no effect on VT 24 hours after infarction. Conclusion: A low dose of levcromakalim has specific antiarrhythmic properties against repolarization-dependent arrhythmias, but it does not affect VTs based on other mechanisms of abnormal impulse formation.     

Natural history of aberrant crypt foci

BACKGROUND: The aberrant crypt focus (ACF) appears to be an important early step in colorectal carcinogenesis. Our objectives were to determine the natural history of ACF in a surgical model. METHODS: The natural history of ACF was followed by marking the lesions in vivo with tattoos. Rats were given four weekly injections of azoxymethane (AOM; 20 mg/kg). One hundred days after the first injection of AOM, rats were anesthetized, and individual aberrant crypt focus was identified by staining with methylene blue. A 3× 3 mm area, identifying one large (4–8 crypts) ACF was marked with a tattoo dye in each colon. Control animals received saline or AOM injections and were tattooed in areas without ACF. At 200 days, colons were examined for the presence of macroscopic lesions. RESULTS: A total of 54 tumors were found in the study group of 38 animals, and 21 of these were in the transverse and proximal descending colon. The marked areas (all in transverse and proximal descending colon) yielded 6 tumors and 2 ACF, but in 30 instances no abnormality was noted. Probability of observing a tumor in the 3×3 mm area of the colon that was identified as containing ACFs was 17 times greater than expected from the observed tumor rate in approximately the same zone (16 vs. 1.7 percent; 95 confidence interval, 10 to 22 and 0.5 to 1.3 percent). Twenty control animals receiving saline had no tumors of epithelial origin. Nine control animals that were carcinogen-treated and tattooed in areas without ACF had no tumors in the marked areas. CONCLUSION: Results thus show regression of many ACF identified early in the carcinogenesis process. Results also support the hypothesis that some ACF are precursor lesions for adenomas and cancers.Supported by S. Lederman Fellowship Foundation, American Physician Fellowship, and, in part, by National Cancer Institute of Canada.     

Mechanism of physiologic versus pathologic ventricular hypertrophy process: Enhanced or depressed myosin ATPase activity and contractility governed by type,degree and duration of inciting stress

Summary Types of hypertrophy, such as the normal development of the left ventricle of new-born lambs, induction of hypertrophy following administration of subhypertensive doses of norepinephrine, and hypertrophy where moderate pulmonic stenosis is the inciting stimulus, are all of a physiologic nature, i.e., cardiac function is elevated and K⁺ stimulated myosin ATPase activity is increased. The K⁺/EDTA stimulated myosin ATPase activity, used as an index of physiologic versus pathologic hypertrophy, may reflect alterations in myosin heavy chains since a large amount of light chains are in the dissociated state with this kinetic system. In experimental conditions where light-chain deficient-myosin was employed there was no corresponding decrease in myosin ATPase activity with the dissociation of light chains, irrespective of the cation activator utilized; there was however a decrease in the enzymatic activity of actomyosin with the loss of light chains. Furthermore, this decrease in actomyosin ATPase activity was partially restored with the reassociation of light chains with light-chain-deficient-myosin. Where excessive hypertrophy occurred, e.g., with moderate pulmonic stenosis, where the right ventricular free wall weight increased 100%, there was a decrease in cAMP content. This may result from the subsequent decrease in stress per sarcomere following massive hypertrophy. Where there was a lesser degree of hypertrophy, e.g., with mild pulmonic stenosis, creating a transitory 30% increase in right ventricular free wall weight, there was no subsequent decrease in cAMP content.Myosin ATPase activity provides a valuable parameter capable of distinguishing physiologic from pathologic ventricular hypertrophy in advanced stages of cardiac diseases. Physiologic hypertrophy is defined as hypertrophy accompanied by normal or augmented myosin ATPase activity and contractile state, whereas pathologic hypertrophy is associated with depressed myosin ATPase activity and contractility without necessarily concordant heart failure. Furthermore we formulate the concept of the dependance of the type of hypertrophy, i.e., physiological versus pathological, on the interdigitation of a combination of a number of defined major determinants, which comprise the degree of ventricular wall stress, the duration of such stress, the nature of the inciting stimulus, as well as the species, age and health of the animal.As example of physiologic hypertrophy, experimental hyperthyroidism serves as one prototype since all myocardial metabolic and mechanical indices are elevated, including contractility and myosin ATPase activity (1). In the study described here we define further examples of physiologic hypertrophy, namely normal development of the left ventricles of newborn lambs, development of the adult dog heart following subhypertensive doses of norepinephrine, and mild as well as moderate pulmonic stenosis. We have designated the varying degrees of pulmonic stenosis as mild, moderate and severe depending on whether the pressure overloaded right ventricle resulted in a transitory increase (2), a sustained increase (3), or a diminished myosin ATPase activity (2), respectively. Thus with mild pulmonary artery banding causing a 50 to 100% rise in right ventricular peak systolic pressure, right ventricular free wall weight increased 30% (2). Moderate elevation of right ventricular peak systolic pressure of 150% resulted in increase of right ventricular free wall weight of 100% (3), whereas severe right ventricular peak systolic pressure rise of 200% caused increased free wall muscle mass of 50% (2). The study of severe pulmonic stenosis indicates that factors other than wall stress determine the degree of hypertrophy.It is important to emphasize that when the hypertrophying stimulus is particularly prolonged and intense, excessive cell growth is elicited with disproportionate biosynthesis of organelles and contractile proteins as well as other subcellular structures, thereby leading to the evolution of pathologic hypertrophy. Pathologic hypertrophy may not only occur in chronic situations but may take place immediately such as in severe experimentally induced pulmonic or aortic stenosis (2). Pathologic hypertrophy is characterized by decreased myosin ATPase activity (2), diminished cAMP content (3) and depressed contractile function (4) as observed with severe pulmonary artery or aortic banding. These metabolic and mechanical features of pathologic hypertrophy may be the result of tissue acidity (5) and thus increased tissue PCO₂ (6).

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Mechanismus der physiologischen und pathologischen Ventrikelhypertrophie: Erhöhte oder verminderte Myosin-ATPase-Aktivität und Kontraktilität in Abhängigkeit von Typ, Grad und Dauer der auslösenden Belastung

Zusammenfassung Hypertrophietypen, wie die normale Entwicklung des linken Ventrikels neugeborener Lämmer, Hypertrophie nach Verabfolgung von Noradrenalin sowie bei mäßiger Pulmonalstenose, sind als physiologische Hypertrophie zu bezeichnen, d. h., die Herzfunktion ist gesteigert und die K⁺-stimulierte Myosin-ATPase-Aktivität ist erhöht. Die K⁺/EDTA-stimulierte ATPase-Aktivität wird als eine Möglichkeit zur Abgrenzung einer physiologischen Hypertrophie gegenüber einer pathologischen Hypertrophie gewertet und kann Änderungen der schweren Ketten des Myosins widerspiegeln, da die leichten Ketten zum großen Teil dissoziiert sind. In Experimenten, in denen Myosin ohne leichte ketten benutzt wurde, kam es nicht zu einer korrespondierenden Abnahme der Myosin-ATPase-Aktivität mit der Dissoziation der leichten Ketten, unabhängig von dem jeweils benutzten kationischen Aktivator. Es kam jedoch mit dem Verlust von leichten Ketten zu einem Abfall in der enzymatischen Aktivität von Aktomyosin. Weiterhin wurde diese Minderung der Aktomyosin-ATPase-Aktivität teilweise rückgängig gemacht bei Reassoziierung der leichten Ketten mit dem restlichen Myosinmolekül. Wenn eine exzessive Hypertrophie zustande kam, z. B. bei mäßiger Pulmonalstenose mit einem Gewichtsanstieg der freien Wand des rechten Ventrikels um 100%, kam es zu einem Abfall des cAMP-Gehalts. Dies könnte mit einer Hypertrophie-bedingten Minderung der mechanischen Spannung zusammenhängen. Bei geringeren Hypertrophiegraden, z. B. bei milder Pulmonalstenose mit transitorischem Gewichtsanstieg des rechten Ventrikels um 30%, war kein Rückgang des zyklischen AMP-Gehalts zu verzeichnen.

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Paper, presented at the Erwin Riesch Symposium, Tübingen, April 3–7, 1979

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With 2 figures and 2 tables

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This study was supported by NIH-ROI-HL-23518-01 from the National Institutes of Health, Bethesda, Maryland.     

A gamma-detecting probe for radioimmune detection of CEA-producing tumors

The detection of tumors with radiolabeled antibodies against CEA is possible; however, current nuclear medicine scanning cameras rarely detect tumors smaller than 2 cm in diameter. One of the limitations to tumor detection is the inability to place a detecting camera near a deeply seated intra-abdominal tumor. A hand-held gamma-detecting probe, suitable for intraoperative use, was designed to locate radioactive tumors. Experimental work with CEA-producing colon tumor xenografts in nude mice suggests this probe is more sensitive than external scanners in detecting small tumors. A case report documents the clinical use of this new intraoperative probe. Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 5–9, 1983. Supported by PHs Grant No. CA 18016 awarded by the National Cancer Institute, DHHS.     

Whole abdominal radiotherapy and concomitant 5-fluorouracil as adjuvant therapy in advanced colon cancer

PURPOSE: This analysis was undertaken to assess whole abdomen radiation therapy and concurrent 5-fluorouracil for toxicity and patterns of failure in high-risk colon cancer patients after curative surgical resection. METHODS: Eighteen patients were treated adjuvantly after curative resection. Four patients (22 percent) had Stage B and 14 (78 percent) had Stage C disease. Histology was poorly differentiated in 4 (22 percent) and moderately differentiated in 14 (78 percent) patients. Four patients received whole abdominal radiation only, 30 Gy at 1 Gy/day. Fourteen patients had an additional locoregional boost of 9.6 to 16 Gy at 1.6 Gy/day. The liver received 19.8 Gy at 0.67 Gy/day. 5-Fluorouracil was given as a continuous infusion during therapy. RESULTS: With a median follow-up of three years, 6 of 18 (33 percent) patients have relapsed. Failure occurred locally in 3 of 18 (17 percent) and distantly in 4 of 18 patients (22 percent). Four of six (67 percent) failures occurred in the liver. The five-year actuarial survival and disease-free survival were 78 percent and 66 percent, respectively. Median elapsed time on radiotherapy was 73 days, with 5 of 18 patients (28 percent) requiring two or more weeks of unplanned treatment breaks. Acute Grade 3 to 4 toxicity (diarrhea, leukopenia) occurred in 3 of 18 patients (17 percent), with late complications (bowel obstruction) occurring in 2 of 18 patients (11 percent). CONCLUSIONS: Whole abdominal radiotherapy with concomitant 5-fluorouracil appears to improve local control but not to prevent liver metastases. Significant toxicity resulted in frequent interruption of therapy and protracted its course. Whether this adjuvant regimen impacts on survival or offers an advantage over locoregional irradiation remains to be studied.     

Akute Pankreatitis

Acute pancreatitis is a potentially fatal disease with individually differing expression of systemic involvement. For this reason early diagnosis with subsequent risk stratification is essential in the clinical management of this frequent gastroenterological disorder. Severe forms of acute pancreatitis occur in approximately 20?% of cases often requiring intensive care monitoring and interdisciplinary therapeutic approaches. In the acute phase adequate fluid replacement and sufficient analgesic therapy is of major therapeutic importance. Concerning the administration of antibiotics and the nutritional support of patients with acute pancreatitis a change in paradigms could be observed in recent years. Furthermore, endoscopic, radiological or surgical interventions can be necessary depending on the severity of the disease and potential complications.     

Mediastinal microdialysis in the diagnosis of early anastomotic leakage after resection for cancer of the esophagus and gastroesophageal junction

Background

Anastomotic leakage (AL) after gastroesophageal resection for cancer is a serious complication. The aim was to evaluate mediastinal microdialysis in the detection of AL before clinical symptoms.

Methods

Sixty patients were included. Samples were collected every 4 hours in the 1st 8 postoperative days and analyzed for several metabolites.

Results

Forty-four patients had an uncomplicated postoperative recovery, 7 developed anastomotic-related complications, and 5 developed major nonanastomotic-related complications. Six patients were excluded (early catheter malfunction and reoperation). Logistic regression model on several metabolites demonstrated a 100% sensitivity, specificity, and positive and negative predictive values regarding the diagnosis of anastomotic complications within postoperative day 7. However, as independent markers, none of the measured metabolites were able to predict AL.

Conclusion

The diagnosis of anastomotic-related complications before clinical symptoms seemed possible by mediastinal microdialysis, but the diagnosis should be based on an interpretation of several metabolic events.     

Single institutional experience using biological mesh for abdominal wall reconstruction

Background

Complex ventral hernias remain a challenge. We present a study evaluating outcomes of complex ventral hernia repair using human-derived acellular dermal matrix (AlloDerm) and porcine-derived acellular dermal sheet (Permacol).

Methods

A retrospective review of 251 patients undergoing complex hernia repair was performed. Primary outcome was hernia recurrence; and secondary outcomes included early and late complications and mortality.

Results

Recurrence for Permacol versus AlloDerm was 32% versus 47% (P = .02). There was a difference in early complications (48% vs 30%, P = .007) and also late complications (30% vs 21%, P = .16) of Permacol versus AlloDerm. Overall survival was 85% for the Permacol group versus 78% for the AlloDerm group (P = .23). Recurrence for Permacol versus AlloDerm for underlay technique was 19% versus 22% and that for bridging technique was 44% versus 57%.

Conclusion

There exists a high complication rate from both Permacol and AlloDerm in complex ventral hernia repair especially when used as a fascial bridge.