Investigations on organ-specific metabolism and genotoxic effects of the urinary bladder carcinogen N-nitrosobutyl-3-carboxypropylamine (BCPN) and its analogs N-nitrosodibutylamine (NDBA) and N-nitrosobutyl-4-hydroxybutylamine (4-OH-NDBA)

N-Nitrosodibutylamine (NDBA) and its omega-oxidized metabolites N-nitrosobutyl-4-hydroxybutylamine (4-OH-NDBA) and N-nitrosobutyl-3-carboxypropylamine (BCPN) are potent urinary bladder carcinogens. To study putative organ specific activation of BCPN, its alpha-oxidation by liver and urinary bladder microsomal fractions was investigated in comparison to NDBA and 4-OH-NDBA. Additionally, induction of DNA single strand breaks (SSB) was monitored in hepatocytes and in a human lymphoblastoid cell line (Namalva) in the presence and absence of external metabolic activation, including N-nitroso-t-butyl-n-butylamine as a negative control. BCPN was alpha-hydroxylated and dealkylated at both alkyl chains in small rates (about 1 nmol x mg protein-1 x 60 min-1) by microsomes from rat liver and pig urinary bladder epithelium. NDBA and 4-OH-NDBA were dealkylated at similarly low rates by pig urinary bladder microsomes, in strong contrast to the high debutylation rates observed for rat liver microsomes. Correspondingly, SSB induction by NDBA and 4-OH-NDBA was observed in Namalva cells with NDBA and 4-OH-NDBA in the presence of PB-induced rat liver microsomes but not with urinary bladder microsomes or without external activation. BCPN did not induce DNA-damage in Namalva cells (with or without external activation) or in rat hepatocytes. Significant induction of sister chromatid exchanges (SCEs) and micronuclei, however, was observed in Namalva cells after incubation with NDBA and BCPN. Our data suggest activation of BCPN via alpha-oxidation in the urinary bladder, even though activation rate in-vitro is so low that a positive response is not detectable by several short-term tests.     

Superficial branch of the radial nerve piercing the brachioradialis tendon to become subcutaneous: an anatomical variation with clinical relevance.

We dissected 20 preserved Caucasian cadaveric upper limbs looking at the relation of the superficial branch of the radial nerve (SBRN) to the brachioradialis tendon. SBRN emerged from deep to superficial position by piercing the brachioradialis tendon near its dorsal border in four limbs. The resulting dorsal tendinous band compressed the nerve and prevented longitudinal gliding movement during ulnar flexion. This is likely to increase the risk of chronic compression neuropathy (Wartenberg's syndrome). In two of these four limbs, there was a communication between the SBRN and lateral cutaneous nerve of the forearm. No such communication was found in the remaining 16 forearms. This communication could contribute to the minimal area of sensory loss observed in Wartenberg's syndrome. We recommend that this anatomical anomaly is looked for and if present dealt with during surgical treatment of Wartenberg's syndrome, as it is likely to predispose to chronic compression neuropathy.     

Chronic cyclosporine nephrotoxicity in renal transplantation

Although extensively studied, the pathophysiologic characteristics of chronic cyclosporine (CsA) nephrotoxicity are still far from being completely understood. The recognition of chronic CsA nephrotoxicity in allografted kidneys is hampered by a lack of easily assessable sensitive and specific markers. Long-term results of CsA withdrawal trials and trials that evaluated CsA sparing or withdrawal after the diagnosis of chronic allograft nephropathy (CAN) have shown that chronic CsA nephrotoxicity has a more important role in the etiology of late transplant dysfunction than appreciated before. Various hypotheses have explained the renal structural changes of chronic CsA nephrotoxicity including ischemia, cellular toxicity, and the stimulation of renal fibrosis by growth factors or cytokines. Possible ways to prevent chronic CsA nephrotoxicity include improved therapeutic drug monitoring and CsA withdrawal or avoidance. Patients with aspecific CAN in late biopsy may benefit from withdrawal of CsA or a reduction of its dose. Current knowledge is being discussed. It is concluded that in the near future more strategies are likely to be used to prevent loss of allograft function as a result of drug toxicity.     

Multidisciplinary approach in the long-term management of intrahepatic stones: Indian experience.

BACKGROUND: Intrahepatic stones, though common in East Asia, are uncommon in India. There is paucity of data from India regarding the treatment and long-term outcome of patients with intrahepatic stones. METHODS: We retrospectively analyzed medical records of 35 patients with intrahepatic stones who had been treated surgically. Endoscopic biliary drainage had been used in patients who presented with acute cholangitis. Intraoperative stone clearance was confirmed by choledochoscopy and intraoperative cholangiography. Outcome of surgery, frequency and subsequent management of recurrent intrahepatic stones, and factors associated with stone recurrence and cholangitis were analyzed. RESULTS: Twenty-one (60%) patients had bilobar disease. Eight patients underwent hepatectomy and 16 hepatico-jejunostomy with access loop; 12 of these were jejuno-duodenal anastomoses. Postoperative morbidity was observed in 10 patients (29%). Recurrence of stones occurred in 12 patients (34%) and cholangitis in 9 patients (26%). Presence of bilobar disease and associated biliary strictures were associated with recurrent cholangitis (p< 0.05). Two patients (6%) required re-operation for recurrent cholangitis. Complete removal of recurrent stones using conventional endoscope was possible through jejuno-duodenostomy in all 5 cases who had this type of access loop construction. CONCLUSION: Surgical treatment for intrahepatic stones depends on the site of involvement. Construction of a jejuno-duodenal access loop in patients with bilobar disease and intrahepatic strictures is helpful in facilitating postoperative stone clearance. A multidisciplinary approach is beneficial especially when the disease is bilobar and recurrent in type.     

Constancy and variability of gallbladder ejection fraction: impact on diagnosis and therapy.

The main objective of this study was to test the constancy and variability of gallbladder (GB) ejection fraction (EF) in long-term studies to (a) determine whether EF ever becomes normal once it is low, (b) determine how long it takes for the EF to become abnormal once it is found to be normal, (c) explore the cause of low EF, and (d) define objective parameters for biliary and nonbiliary abdominal pain. METHODS: Fifty-two patients (42 women, 10 men) who underwent quantitative cholescintigraphy twice (total studies, 104), over a mean period of 38.54 mo between studies, were chosen for retrospective analysis. They were divided into the following groups: control (n = 13; nonbiliary abdominal pain), chronic acalculous cholecystitis (CAC) (n = 27; biliary abdominal pain), chronic calculous cholecystitis (CCC) (n = 6; biliary abdominal pain), and opioid (n = 6; nonbiliary abdominal pain). The last group had received an opioid before cholecystokinin-8 (CCK-8) infusion in one study but not in the other study. A GBEF value of > or =35% was considered normal with a 3-min infusion and > or =50% as normal with a 10-min infusion of CCK-8. RESULTS: The mean GBEF value was reproducible between the 2 sequential studies in the control group (66.0% +/- 20.5% vs. 73.9% +/- 17.7%), CAC group (24.4% +/- 22.3% vs. 16.9% +/- 10.9%), and CCC group (20.8% +/- 20.9% vs. 27.5% +/- 34.5%) but not in the opioid group (14.8% +/- 14.6% vs. 56.5% +/- 31.7%). The severity of GBEF reduction in CAC increased with time: 7.2% +/- 8.1% within 12 mo, 16.1% +/- 14.9% in 13-47 mo, and 23.5% +/- 21.3% in 48-168 mo. None of the 27 patients with CAC developed a gallstone as detected by ultrasound during the study period. In 5 patients with CAC, a mean period of 52.6 +/- 28.9 mo was required for conversion from normal to a low EF. CCK-induced cystic duct spasm is the etiology for low EF in both CAC and CCC. CONCLUSION: Normal and low GBEF values are reproducible in long-term studies. Once the EF reaches a low value, it does not return to normal, and a normal value requires many years to become abnormal. CCK-induced cystic duct spasm is the cause of low GBEF in CAC and CCC, and the severity of EF reduction is similar for both. Exclusion of opioid intake immediately before the study is critical before attributing a low GBEF value to an irreversible GB motor dysfunction.