Replacement of cholesterol gallstones by murideoxycholyl taurine gallstones in prairie dogs fed murideoxycholic acid

The effect of two hydrophilic bile acids, murideoxycholic acid (3 alpha,6 beta-dihydroxy-5 beta-cholanoic acid) and ursodeoxycholic acid, on cholesterol and bile acid metabolism and hepatic pathology and gallstone composition was studied in the prairie dog. Cholesterol gallstones were induced by feeding a diet containing 1.2% cholesterol for 75 days. The animals were divided into six groups, and gallstone regression was studied as follows: groups 2 and 5, chow plus 0.2% cholesterol; groups 3 and 6, chow plus 0.2% cholesterol plus 0.15% ursodeoxycholic acid; groups 4 and 7, chow plus 0.2% cholesterol plus 0.15% murideoxycholic acid. Animals in groups 2 to 4 were killed after an additional 6 wk; animals in groups 5 to 7 were killed after an additional 12 wk. Gallstone dissolution did not occur in any group. The gallstones in groups 2, 3, 5 and 6 were typical cholesterol aggregates, as determined by polarized light microscopy and Fourier transform infrared spectrometry. The gallstones of the murideoxycholic acid group were large, solitary, dark stones that appeared radiopaque under 22 kVp x-ray examination. Scanning electron microscopy showed that in these stones the cholesterol crystals had been replaced by an amorphous material, both within the stone and on the stone surface. Chemical analysis indicated that at the end of 12 wk the calcium/sodium salt of the taurine conjugate of murideoxycholic acid (murideoxycholyl taurine) comprised 70% of the stones; protein, cholesterol and small amounts of other bile salts were also present. In vitro studies confirmed the insolubility of the sodium and calcium salts of murideoxycholyl taurine. These studies indicate that the hydrophilic bile acids, murideoxycholic acid and ursodeoxycholic acid, did not achieve gallstone dissolution under the conditions used. In the animals fed murideoxycholic acid, an insoluble calcium salt of murideoxycholyl taurine replaced cholesterol as the major constituent of gallbladder stones. This is the first example of an insoluble dihydroxy taurine-conjugated bile acid; administration of the unconjugated bile acid induced precipitation of a kind of gallstone not previously reported. The final result was transformation of cholesterol stones to bile salt stones.     

Repeat hepatic resections for metastatic colorectal cancer.

OBJECTIVE: The authors weighed the risks and benefits of repeat liver resections for colorectal metastatic disease. METHOD: In the 6-year period between January 1985 and June 1991, 499 patients underwent liver resections for colorectal metastases at the Memorial Sloan-Kettering Cancer Center. Of these, 25 patients had repeat surgical resections for isolated recurrent disease to the liver. The clinical data for these patients were reviewed. RESULTS: The median interval between the two resections was 11 months. There were no perioperative deaths, and the complication rate was 28%. Median follow-up after the second liver resection is 19 months, with median survival of 17 months for nonsurvivors. Although the median survival after the second resection is 30 months, 20 of the 25 patients have had recurrences with a median disease-free interval of only 9 months. No characteristic of primary or metastatic disease predicted outcome, including time between presentation of the primary and development of liver metastases, disease-free interval after the first liver resection, and bilobar liver involvement. CONCLUSIONS: Although repeat liver resections can be performed safely and improves survival, the likelihood of cure from such resection therapy is low. This likelihood of further recurrences encourage studies of adjuvant or alternative treatments of this population.     

Early laparoscopic cholecystectomy for acute cholecystitis

Background: The timing of laparoscopic cholecystectomy for acute cholecystitis remains controversial. Methods: One hundred ninety-four patients with acute cholecystitis were reviewed. The conversion rates for the various number of days of symptoms before surgery were analyzed. The conversion rate dramatically increased from 3.6% for those patients with 4 days of symptoms to 26% for those patients with 5 days of symptoms. The mean number of days of symptoms prior to surgery in those patients who underwent successful laparoscopic cholecystectomy was 4.1 as compared to 8.0 in those patients who required open cholecystectomy (p < 0.0001). Based on this data the patients were divided into two groups. Group 1 consisted of 109 patients who underwent laparoscopic cholecystectomy within 4 days of onset of symptoms and group 2 consisted of 85 patients who underwent laparoscopic cholecystectomy after more than 4 days following onset of symptoms. Results: The conversion rate from laparoscopic to open cholecystectomy was 15%. The conversion rate for group 1 was 1.8% as compared to 31.7% for group 2 (p < 0.0001). Indications for conversion were inability to identify the anatomy secondary to inflammatory adhesions (68%), cholecystoduodenal fistula (18%), and bleeding (14%). The major complication rate for group 1 was 2.7% as compared to 13% for group 2 (p= 0.007). The mortality rate for all patients with attempted laparoscopic cholecystectomy for acute cholecystitis was 1.5%. The average procedure time for group 1 was 100 ± 37 min vs 120 ± 55 min in group 2. The average number of postoperative hospital days in group 1 was 5.5 ± 2.7 days as compared to 10.8 ± 2.7 days in group 2. Conclusions: We advocate early laparoscopic cholecystectomy within 4 days of onset of symptoms to decrease major complications and conversion rates. This decreased conversion rate results in decreased length of procedure and hospital stay. Received: 28 March 1996/Accepted: 12 September 1996     

Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate An experimental study in a rat model

We have previously demonstrated in a rat model that the lumbar intrathecal injection of 0.02 ml 6.3% magnesium sulphate, a concentration iso-osmolar with rat plasma, produces a state of spinal anaesthesia and general sedation which reversed completely after 6 h, without evidence of neurotoxicity, immediately or during the week thereafter. Using the same model and five groups of six animals in each, we administered the same volume and concentration of magnesium sulphate and compared its clinical effects with those of 0.02 ml 12.6% magnesium sulphate, 0.02 ml 2% lignocaine and 0.02 ml 0.9% sodium chloride solution, given as a series of 15 injections on alternate days for a period of 1 month. The animals were then killed and their spinal cords and meninges examined histologically. No significant differences were noted in the times of onset, durations of sensory and motor blockade and the times to full recovery throughout the entire period of 1 month's observation in the animals receiving intrathecal 6.3% magnesium sulphate. In the group receiving 12.6% magnesium sulphate, the time of onset of sensory and motor blockade was shorter and the duration of both parameters was significantly longer than in the former group. Full clinical recovery and resumption of normal eating and drinking took place in both groups throughout the entire series of 15 successive intrathecal injections. Identical, mild, uniform histopathological changes in the spinal cord were seen in all the five groups, including the group in which only the intrathecal catheter was implanted. The complete recovery and benign consequences of repeated intrathecal injections of iso-osmolar magnesium sulphate in a rat model indicate a lack of neurotoxicity and provide an impetus for further trials in larger animal species, before initial clinical trials of this substance, given intrathecally, in humans.     

Dynamic gadolinium-enhanced echo-planar MR imaging of the liver: Effect of pulse sequence and dose on enhancement

To develop guidelines for clinical magnetic resonance imaging of the liver, the authors undertook an animal study to investigate the effect of dose and pulse sequence on liver signal intensity in gadopentetate dimeglumine—enhanced echo-planar imaging. Serial imaging of the liver was performed in anesthetized rats after intravenous administration of five different doses (0.01, 0.05, 0.1, 0.2, and 0.5 mmol/kg) of contrast agent, with six different pulse sequences. The results show that gadopentetate dimeglumine—enhanced echo-planar images obtained during the perfusion phase can yield either positive (due to increased T1 relaxation rates) or negative (due to susceptibility-induced increased T2 relaxation rates) liver enhancement depending on choice of pulse sequence and dose. At the current clinically recommended dose of 0.1 mmol/kg, maximal liver signal enhancement was seen with a T1-weighted inversion-recovery sequence, while maximal liver signal diminution was seen with a T2*-weighted gradient-echo sequence. The authors conclude that gadopentetate dimeglumine—enhanced echo-planar imaging can provide T1, T2, and T2* contrast that may be exploited for both lesion detection and lesion characterization.     

Ninety-Six Five-Year Survivors After Liver Resection for Metastatic Colorectal Cancer

Background: Studies have consistently confirmed the benefit of liver resection for metastatic colorectal cancer. Few reports, however, have a long enough followup or sufficient 5-year survivors to study the clinical course of patients beyond 5 years.

Study Design: From July 1985 through December 1991, 456 patients underwent liver resection for colorectal metastases. Ninety-six actual 5-year survivors (21%) were identified and their clinical course retrospectively reviewed.

Results: Five-year survivors (n = 96) were more likely to have a Duke’s B primary colorectal carcinoma, fewer than four metastatic lesions, unilobar disease, and a negative histologic margin when compared with patients not surviving 5 years (n = 298). Forty-four (46%) of the 96 five-year survivors had a recurrence after hepatectomy. Of these 44, 19 (43%) were rendered disease free after further treatment. Overall, 71 of the 96 five-year survivors were free of disease at last followup. The actuarial 10-year survival of this group was 78%.

Conclusions: Patients that are disease free 5 years after liver resection are likely to have been cured by liver resection. Patients should be aggressively followed for recurrence because of the potential for further treatment and longterm survival.     

Differential effects of monoclonal antibodies to tumor necrosis factor alpha and gamma interferon on induction of hepatic nitric oxide synthase in experimental gram-negative sepsis.

To investigate the stimuli required for the induction of nitric oxide synthase (NOS) in sepsis, we have analyzed the levels of this enzyme in the livers of mice infected with a 90% lethal dose of Escherichia coli in a model of gram-negative sepsis. Hepatic NOS levels are markedly induced in this model, with peak values occurring 12 to 22 h following infection. Treatment with TN3-19.12, a neutralizing monoclonal antibody to tumor necrosis factor alpha (TNF-alpha), resulted in complete protection from death in this model of sepsis but had no significant effect on the level of induction of hepatic NOS. Treatment with H22, a monoclonal antibody to gamma interferon (IFN-gamma), also gave significant protection against death and, in addition, did lead to a decrease in the level of induction of the hepatic NOS. Treatment of mice with pure TNF-alpha (0.2 microgram), IFN-gamma (2,000 U), or a combination of the two did not induce the hepatic NOS, but treatment with the combination led to significant mortality (probability of survival at 22 h, 0.32). Thus, the level of induction of NOS within the liver either in sepsis or by the coadministration of TNF-alpha and IFN-gamma does not correlate with death.     

Acquired cystic disease in chronically rejected renal transplants.

Acquired cystic disease has been documented to complicate most forms of chronic renal damage; it has only infrequently been described in transplanted kidneys. Five patients with noncystic ESRD and chronically rejected transplants in which acquired cystic disease arose are reported. The diagnosis of acquired cystic disease was established in examination of transplant nephrectomies from four patients and a core biopsy from the fifth. The allografts were in place from 44 to 80 months; three patients were treated with hemodialysis before the diagnosis of acquired cystic disease, whereas two received peritoneal dialysis. Three of the four patients evaluated had cysts in the native kidneys. Although papillary hyperplasia of lining epithelium was evident in four specimens, only one kidney was the site of neoplasms in the form of multiple small tubular adenomas. No malignant neoplasms were noted in this study or in the few similar previous ones; however, it is possible that chronically rejected transplanted kidneys may harbor neoplasms with the same malignant potential as those in acquired cystic disease in native kidneys.