Raffaele Tritapepe

SELECTIVE AND EARLY INCREASE OF IL-1 INHIBITORS, IL-6 AND CORTISOL AFTER ELECTIVE SURGERY

After trauma, inflammatory, immunological and hormonal changes are well documented. Surgical intervention is a form of programmed trauma. Through the study of surgical patients, changes in early endogenous mediators of inflammation, immune response and tissue repair can be investigated. Here we analysed changes in serum levels of IL‐1 inhibitors, IL‐1β, IL‐6, tumour necrosis factor‐alpha (TNF‐α) and cortisol in patients undergoing elective surgery. C‐reactive protein (CRP) was measured as a marker of the acute‐phase response. Rises in serum levels of IL‐1 inhibitors. IL‐6 and cortisol were detected as early as 1 h after the intervention. Peak levels were reached between 2 and 5 h. Serum levels of IL‐6 and cortisol remained elevated for several days implying a persistent production. Serum levels of IL‐1 and TNF did not change after the intervention. CRP levels peaked on day 2. The communication system sustained by endogenous mediators is activated after surgery as shown by selective changes in IL‐1 inhibitors, IL‐6 and cortisol. These mediators have different kinetics in serum and IL‐6 is not the only early mediator detected. Some IL‐1 inhibitors might be involved in the immunological depression observed after major surgery, in the regulation of the inflammatory response or in tissue repair. IL‐6 and cortisol seem to act synergistically to activate the acute‐phase response. A systemic role for IL‐l and TNF is not evident, even if the possibility that these lymphokines may act locally is not ruled out.

Methyl tert-butyl ether fails to dissolve retained radiolucent common bile duct stones.

Methyl tert-butyl ether (MTBE) has been recently proposed as a new therapeutic modality for the dissolution of cholesterol gallstones. To further evaluate efficacy and tolerability of this new litholytic agent, we have administered MTBE to 3 patients with nonobstructive radiolucent common bile duct stones after recent surgery. Methyl tert-butyl ether (8-11 ml/day) was infused after aspiration of bile via a Teflon catheter inserted through the postoperative T tube. Gentle aspiration and reinfusion were performed continuously to generate stirring. The total amount of MTBE retrieved during the entire procedure was equivalent to approximately 30% of the volume infused. In all cases, MTBE failed to dissolve the radiolucent stones, which were then dissolved with continuous infusion of monooctanoin via the biliary catheter. The characteristic odor of MTBE was detected on the breath of the patients, and nausea and somnolence developed during the treatment. Serum hepatic and pancreatic enzymes did not change after MTBE. In the third subject, who received 11 ml/day of MTBE for 2 consecutive days (total of 22 ml), histologic evidence of duodenitis was found around the papilla. In our opinion, the lack of efficacy of MTBE in dissolving retained radiolucent common bile duct stones was mainly related to its leakage from the common bile duct into the duodenum and the ensuing local chemical toxicity and systemic absorption. As MTBE needs a persistent stone-solvent contact to exert its litholytic action and, at the same time, its toxicity prevents the infusion of larger doses, MTBE use should be restricted to stones placed in closed chambers, such as the gallbladder.

Excision and primary closure of pilonidal sinus using a drain for antiseptic wound flushing

BACKGROUND In the case of pilonidus sinus treated with primary intention surgery the uneventful healing is still difficult to obtain, as indirectly proven by the number of different procedures that have been suggested, such as cyst excision with or without primary closure, excision followed by marsupialisation, and excision followed by skin flap transposition. The procedure described here involves excision and primary closure, with a drain being used to flush the operative cavity with an antiseptic solution. METHODS Two hundred and forty-three patients (173 men and 70 women) were treated by excising the pilonidal sinus and placing a 12F suction drain at the base of the wound, with its tip being brought out in the left gluteal region at least 5 cm laterally to the lower end of the suture. Suction was stopped on the first postoperative day and the drain was cut just above the skin. On day 2, a 5F catheter was inserted through the drain and the cavity was flushed with an antiseptic solution followed by sterile saline solution; the same treatment was repeated on days 4 and 6. The drain was removed on day 8 or 9, some of the stitches on day 8 or 9 and the rest on day 9 or 10. The surgery was performed on a day hospital basis in 207 cases; the remaining 36 were hospitalized overnight and discharged on the following day. RESULTS Healing was always by first intention, with none of the 243 patients experiencing any complications. The postoperative follow-up now ranges from 5 to 15 years, and there have not been any recurrences. CONCLUSIONS The drainage of blood from the bottom of the wound and the use of antiseptic/saline flushing are essential for primary intention healing and the avoidance of recurrences.

S-adenosyl-l-methionine protection against α-naphthyl- isothiocyanate-induced cholestasis in the rat

Abstract The effect of S -adenosyl- l -methionine (SAMe) on cholestasis induced by α-naphthylisothiocyanate (ANIT) was studied in rats. SAMe significantly attenuated both bile flow impairment and elevated values of serum bilirubin, glutamic pyruvic transaminase and alkaline phosphatase in ANIT-treated animals. These results suggest that SAMe protects the rat liver against the toxic effects of ANIT.

Decreased Blood Levels of Ethanol and Acetaldehyde by S-Adenosyl-L-Methionine in Humans

In view of the protective effects of SAM on alcohol-induced fatty liver degeneration, an investigation has been carried out to see if this compound accelerates the clearance of ethanol and acetaldehyde in humans. Both parameters were significantly lower after SAM, indicating the capability of exogenous SAM to favour the inactivation of ethanol without increasing blood levels of acetaldehyde.

Bile secretion and liver microsomal mixed function oxidase system in mice with griseofulvin-induced hepatic protoporphyria

Administration of 2.5% griseofulvin in the diet to male CD1 mice produced protoporphyria and cholestasis. Protoporphyria became evident as early as after 10 days of treatment, whereas cholestasis, expressed in terms of total bile flow reduction, developed only after 45 days of griseofulvin. Bile flow impairment was due both to the length of treatment and to the severity of liver protoporphyria. Griseofulvin administration was also associated with a significant modification of the relative amounts of hepatic microsomal cytochromes P-450 and b5, a loss in concentration/mg of protein of cytochrome P-450 and a concomitant increase of b5. Despite these changes, the activity of aniline hydroxylase expressed per mg of microsomal protein, assessed in vitro, was not modified.

Inhibition of lymphocyte function by a naturally occurring nucleoside: 5′-Methylthioadenosine (MTA)

The link between immunodeficiencies and nucleoside metabolism is exemplified by the inherited deficiencies of adenosine deaminase and purine nucleoside phosphorylase which are associated with an abnormal development of the immune system. In this report we show that high doses of methylthioadenosine (MTA), a natural purine nucleoside, inhibit both the mitogen-induced blastogenesis of human peripheral blood lymphocytes (PBL) and the pokeweed mitogen (PWM)-driven in vitro immunoglobulin synthesis by PBL in a non-toxic and reversible fashion. Our data support the view that both T and B cells are sensitive to MTA inhibition and that PWM-driven Ig production is more affected by MTA than the mitogen-induced PBL proliferation. The observation that MTA causes an evident inhibition of in vitro PWM-driven Ig secretion when added four days after the start of the cultures suggests that MTA can exert its activity not only on proliferation but also on differentiation of B cells.

3-hydroxy-3-methylglutaric acid (HMGA) reduces dietary cholesterol induction of saturated bile in hamster

3-Hydroxy-3-methylglutaric acid (HMGA) is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAR) and strongly reduces cholesterol biosynthesis both in vitro and in vivo. Since the effects of this compound on biliary lipid composition are hitherto unknown, we have investigated whether it prevents dietary cholesterol induction of saturated bile in the hamster. Female Golden Syrian hamsters have been divided into four groups and treated for 10 weeks as follows: I) Standard diet, containing 0.8 mg cholesterol/g food; II) Standard diet plus HMGA (100 mg/kg b.w./day per os); III) Lithogenic diet containing 2.4 mg cholesterol/g food; IV) Lithogenic diet plus HMGA as above. The results indicate that HMGA is effective in reducing both bile cholesterol supersaturation and hypercholesterolemia. Inhibition of hepatic cholesterogenesis at the level of mevalonate synthesis by HMGCoAR and reduction of intestinal cholesterol absorption may be responsible for these effects.

Effect of Ethanol on Biliary Unconjugated Bilirubin and Its Implication in Pigment Gallstone Pathogenesis in Humans

Though some epidemiological investigations support the association between pigment gallstone formation and chronic alcoholism with cirrhosis, little attention has been paid to the influence of alcohol itself on biliary bilirubin secretion, so that the pathogenesis of pigment cholelithiasis in alcoholics is hitherto unknown. On different days we intravenously administered ethanol (0.7 g/kg body weight), diluted with 500 ml of saline, or saline alone to 6 non-obese patients with an indwelling T tube and reestablished enterohepatic bile circulation. At the time of the investigation bile cultures were negative for aerobic and anaerobic bacteria. Ethanol significantly increased biliary unconjugated bilirubin in respect to control values. The phenomenon reached a maximum 2 h after alcohol infusion when the value of unconjugated bilirubin averaged 2.37 +/- 0.30% of total bilirubin in contrast to 0.65 +/- 0.14% in control conditions (p less than 0.01), and subsided 6 h after the end of ethanol infusion. Since increased amounts of biliary unconjugated bilirubin predispose to pigment stone formation, it can be speculated that alcohol contributes to pigment cholelithiasis pathogenesis by enhancing the biliary concentrations of this form of pigment.

Acute ethanol administration increases biliary concentrations of total and unconjugated bilirubin in rabbits

Epidemiological investigations have revealed that alcoholic cirrhosis is associated with a high frequency of pigment gallstones, but only scantly information is available on the effects of ethanol on biliary secretion of bilirubin. We have injected intravenously 1.0 and 1.5 g/kg body wt of ethanol into six cholecystectomized rabbits with a common bile duct fistula. Experiments were performed ten days after surgery and a stream-splitting apparatus was interposed in the circuit in order to withdraw continuously biliary samples without interruption of enterohepatic bile circulation. Analysis of hourly data showed that both ethanol doses significantly increase the biliary concentration of total bilirubin, without affecting bile flow and lipid composition. Alcohol also promoted the efflux of unconjugated bilirubin into bile. The maximum effect occurred within the first 5 hr following alcohol administration. Thereafter the bile returned to normal. Since excessive concentrations of biliary unconjugated bilirubin favor pigment gallstone development, it can be speculated that alcohol acts as a risk factor for pigment lithiasis by enhancing the biliary levels of this form of pigment.