Montserrat Elena

COMPARISON OF RIFAMPICIN WITH PHENOBARBITONE FOR TREATMENT OF PRURITUS IN BILIARY CIRRHOSIS

The anti-pruritic effects of rifampicin (10 mg/kg) and phenobarbitone (3 mg/kg) were assessed in 22 patients with primary biliary cirrhosis in a crossover randomised clinical trial. Each agent was given for 14 days, with a 30-day washout period between treatments. 21 patients completed the course of rifampicin and 18 that of phenobarbitone; rifampicin was withdrawn from 1 patient when anaemia and renal failure developed, whereas 3 patients stopped taking phenobarbitone because of a rash and the 4th merely refused the drug. Rifampicin had a greater anti-pruritic effect than phenobarbitone. The symptom improved in 19 patients taking rifampicin and in 8 taking phenobarbitone, the degree of improvement being greater with rifampicin than with phenobarbitone. Pruritus disappeared in 9 patients receiving rifampicin, and three of them were free of itch when switching over to phenobarbitone. Both drugs were equally effective in inducing hepatic microsomal function but rifampicin has the additional effect of reducing cholestasis. Its anti-pruritic effect should be tested in long-term clinical trials.

Gastric mucosal vascular ectasias causing bleeding in cirrhosis

To characterize bleeding from gastric red spots in patients with cirrhosis, three groups of patients were studied: (a) 11 cirrhotic patients bleeding from gastric red spots, (b) 18 nonbleeding cirrhotic patients without gastric red spots, and (c) 13 noncirrhotic patients with endoscopic normal mucosa (controls). Histologic examination of antral biopsy specimens revealed a diffuse capillary ectasia without inflammation in 8 of the 11 cirrhotic patients with gastric lesions. Morphometric analysis disclosed a significantly greater mean mucosal capillary cross-sectional area in cirrhotic patients with gastric lesions (mean +/- SE, 1371 +/- 320 microns2) than in those without gastric lesions (541 +/- 61 microns2) (p less than 0.005) or controls (353 +/- 20 microns2) (p less than 0.001). Hypergastrinemia was detected in 8 of the 11 cirrhotic patients with lesions, in 2 of the 18 cirrhotic patients without gastric lesions, and in none of the controls (p less than 0.001). Gastrin serum levels correlated significantly (r = 0.80) with mean mucosal capillary cross-sectional area in patients with cirrhosis. Pepsinogen I serum levels below 20 ng/ml were observed in 7 of the 11 cirrhotic patients with lesions, in 1 of the 18 cirrhotic patients without lesions, and in none of the controls. These data indicate that bleeding from gastric red spots in patients with cirrhosis is a distinct entity characterized by vascular ectasia of the gastric mucosa. This condition seems to be associated with hypergastrinemia and low serum levels of pepsinogen I.

VCAM-1 and ICAM-1 mediate leukocyte-endothelial cell adhesion in rat experimental colitis

BACKGROUND & AIMS The molecular mechanisms responsible for leukocyte recruitment in experimental colitis are poorly understood. The aims of this study were to measure expression of endothelial intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) and to determine their role in leukocyte recruitment in experimental colitis. METHODS Rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis and control rats were studied 1, 7, or 21 days after treatment. ICAM-1 and VCAM-1 expressions were measured by the double radiolabeled antibody technique. Leukocyte-endothelial cell interactions were determined in colonic venules by fluorescence intravital microscopy. Therapeutic effects of treatment with anti-VCAM-1 antibodies were also assessed. RESULTS Colonic endothelial ICAM-1 was constitutively expressed and did not increase in colitic animals. In contrast, constitutive expression of VCAM-1 was low but markedly increased (6-fold) 1 and 7 days after induction of colitis. Increased colonic expression of VCAM-1 paralleled macroscopic damage score, myeloperoxidase activity, and increased leukocyte adhesion in colonic venules. The latter was significantly decreased by immunoneutralization of ICAM-1 and completely abrogated by immunoneutralization of VCAM-1. Long-term administration of anti-VCAM-1 antibody resulted in significant attenuation of colitis. CONCLUSIONS Induction of colitis in rats by TNBS is followed by up-regulation of endothelial VCAM-1. VCAM-1 and constitutive ICAM-1 are major determinants of leukocyte recruitment to the inflamed intestine.

Abnormal serum free light chain ratio in patients with multiple myeloma in complete remission has strong association with the presence of oligoclonal bands: implications for stringent complete remission definition

The prevalence of an abnormal serum free light chain (FLC) ratio in 34 patients with multiple myeloma in complete response (CR) after hematopoietic stem cell transplantation was studied. Fourteen of 34 patients (41.2%) showed an abnormal FLC ratio. The frequency of abnormal FLC ratio in patients with or without oligoclonal bands was 72.7% versus 26%, respectively (P = .023). The median value of FLC ratio was 2.55 (95% confidence interval, 1.89-3.20) in patients with oligoclonal bands versus 0.87 (95% confidence interval, 0.70-1.04) for those with no oligoclonal bands (P = .011). This is the first report showing that the presence of oligoclonal bands in patients with multiple myeloma in CR frequently results in an abnormal FLC ratio. Because an oligoclonal immune response is associated with a good outcome, our results question the current definition of stringent CR and support that the prognostic impact of oligoclonal bands should be also assessed on multivariate analysis.

Reversibility of exocrine pancreatic failure in chronic pancreatitis

In patients with chronic pancreatitis, the development of exocrine pancreatic failure is generally thought to be an irreversible process. We found evidence to the contrary in a prospective study of 70 patients who were evaluated by endoscopic retrograde cholangiopancreatography and sequential measurements of stool fat, percent urinary PABA excretion, and serum trypsin during a follow-up time period of 1-4 yr. Initial p-aminobenzoic acid (PABA) testing showed exocrine failure in 51 patients, 35 of whom had low serum trypsin levels while 14 (27%) disclosed unexpectedly high trypsin concentrations. Ductal morphology was similar in patients with low and high trypsin values. In 8 of the latter cases, steatorrhea improved and pancreatic function tests became normal after pancreaticojejunostomy in 4 patients, alcohol abstinence in 3 patients, and spontaneous resolution of a pseudocyst in 1 patient. Pancreatic cancer was present in a further 3 patients. Of the 37 patients with low PABA and low trypsin at the outset, there was no improvement of exocrine function in 17 of 18 who were surgically treated. Conservative treatment had a similar effect in another 6 patients who were available for follow-up in this group. The mean duration of symptomatic disease was shorter (p less than 0.001) in patients with low PABA and high trypsin levels (1.4 +/- 1.2 yr) than in those with low PABA and low trypsin levels (4.5 +/- 1.3 yr). The results show that up to 20% of patients with chronic pancreatitis have exocrine pancreatic failure, which is apparently due to early ductal obstruction of a gland with preserved function; this situation can be suspected when low urinary PABA excretion and high serum trypsin levels are simultaneously found; and (c) exocrine failure may be reversible in these patients by using a pancreatic drainage procedure or alcohol abstinence. Such a peculiar pattern of pancreatic function tests may also suggest pancreatic cancer.

Emergence of oligoclonal bands in patients with multiple myeloma in complete remission after induction chemotherapy: association with the use of novel agents.

The emergence of oligoclonal bands is associated with a favorable outcome after autologous stem cell transplantation in multiple myeloma. The aim of this study was to determine the prevalence of immunoglobulin oligoclonality in 33 patients with multiple myeloma in complete remission achieved with primary therapy with either cytotoxic agents (n=18, 54.5%) or new induction regimens incorporating novel drugs (n=15, 45.4%). Eleven patients (33.3%) developed oligoclonal bands. In the group treated with novel agents, this oligoclonal immune response was observed in 60% (9 of 15) of the patients versus only 11.1% (2 of 18) of those given cytotoxic therapy (P=0.003). This is the first report showing a different frequency of oligoclonal humoral response in patients in complete remission achieved after conventional cytotoxic therapy versus induction incorporating novel agents. This difference could be due to a higher antitumor effect associated with the use of novel drugs, a stronger immune reconstitution, or both.

Gastric Vascular Ectasias in Cirrhosis: Association with Hypoacidity Not Related to Gastric Atrophy

To investigate whether hypergastrinemia and low serum levels of pepsinogen I are associated with gastric hypoacidity in cirrhosis with capillary ectasia of gastric mucosa and whether this alteration is secondary to the presence of atrophic gastritis, two groups of patients were studied: 1) 12 cirrhotic patients with diffuse gastric red spots at the endoscopic examination, and 2) 12 cirrhotic patients with endoscopically normal mucosa. Vascular ectasia of the gastric mucosa was histologically confirmed in all patients with gastric red spots. The study of base-line and stimulated acid gastric secretion showed that 9 of 12 (75%) cirrhotics with gastric vascular ectasia had achlorhydria and that 8 of these 9 patients had high base-line gastrin serum levels (greater than 130 pg/ml) and low base-line pepsinogen I serum levels (less than 20 ng/ml). Base-line gastrin and pepsinogen I serum levels were significantly greater and lower, respectively, in patients with gastric vascular ectasias than in cirrhotics without these lesions. None of the patients of either group had complete atrophy in the corpus of the stomach, and only 4 of the 9 cirrhotics with gastric vascular ectasia and achlorhydria had moderate atrophy. These results show that achlorhydria is frequently associated with hypergastrinemia and low pepsinogen I serum levels in patients with cirrhosis and gastric vascular ectasias and suggest that this disturbance is not secondary to a morphologic abnormality of the gastric mucosa.

Epithelial cell hyperproliferation after biliopancreatic reflux into the esophagus of rats

BACKGROUND Chronic reflux of duodenal contents into the esophagus of rats produces severe esophagitis and exerts a co-carcinogenic effect on the proliferating cells by enhancing the formation of nitrosamine-induced esophageal carcinomas. We investigated the effect of the different components of the duodenal reflux on the epithelial cell proliferation of the lower esophagus. METHODS Sprague-Dawley rats underwent three surgical reflux models (biliopancreatic, pancreatic, and biliary) and a sham operation. Animals were sacrificed at 72 hours, 6 weeks, and 9 weeks after the operation. Histology and cell proliferation, determined by ornithine decarboxylase activity, polyamine (putrescine, spermidine, spermine) levels, and proliferating cell nuclear antigen labeling index of the basal and suprabasal layers, were studied in the distal esophagus. RESULTS Both biliopancreatic and pancreatic reflux induced severe esophagitis starting on week 6. Suprabasal proliferating cell nuclear antigen labeling index significantly increased throughout the 9 weeks of the study in the biliopancreatic and pancreatic reflux groups, although this increase was earlier in the former group. Ornithine decarboxylase activity and polyamine levels were significantly increased in the biliopancreatic and pancreatic groups on week 6, decreasing on week 9. CONCLUSIONS Increased esophageal cell proliferation after both biliopancreatic and pancreatic reflux into the lower esophagus may therefore be one mechanism by which duodenal-content reflux stimulates esophageal carcinogenesis in experimental animals.

Natural history and prognostic impact of oligoclonal humoral response in patients with multiple myeloma after autologous stem cell transplantation: long-term results from a single institution

The emergence of an oligoclonal humoral response, resulting in the appearance of a different serum M-protein to that observed at diagnosis is a well-recognized event after autologous stem cell transplantation in multiple myeloma in complete response, and it has been considered to be a benign phenomenon. The aim of the present study was to investigate the incidence, biological characteristics and prognostic value of the oligoclonal bands in patients with myeloma who underwent autologous transplantation at our institution in the last 18 years. We proceed with a retrospective systematic review of all serum and urine immunofixation studies performed in the 211 patients with multiple myeloma who underwent melphalan-based autologous transplantation. Oligoclonal bands were observed in 34% of the patients, with a significantly higher prevalence with the use of novel agents versus conventional chemotherapy in induction (63% vs. 22%; P=0.0001). The incidence of oligoclonal bands was most frequent in non-IgG isotype, particularly in light chain only myeloma. The oligoclonal phenomenon was almost exclusive to patients in complete remission compared to other degrees of response (87% vs. 13%; P=0.0001), and lasted for a median of 1.35 years, persisting during follow up in all patients except in those who relapsed. In prognostic terms, the presence of oligoclonality resulted in a significantly longer progression-free and overall survival. Patients with oligoclonal humoral response lasting for more than one year after transplantation had a significantly longer clinical progression-free and overall survival than those with shorter duration (P=0.008 and P=0.0001, respectively), likely reflecting the importance of a robust humoral immune response.

Myocardial Antioxidant Status in Chronic Alcoholism

BACKGROUND Excessive ethanol intake is one of the most frequent causes of acquired dilated cardiomyopathy in developed countries. The pathogenesis is multifactorial, with the antioxidant imbalance of cardiac muscle being a potential factor. The current study evaluates myocardial antioxidant status in ethanol consumers and its relation to cardiac damage. METHODS The authors assessed superoxide dismutase, glutathione peroxidase, and glutathione reductase enzyme activities as well as the total antioxidant status capacity in myocardial samples obtained from organ donors with sudden death of traumatic or neurological origin. They studied 23 high-dose chronic alcohol consumers, 27 individuals with long-standing hypertension, and 11 healthy controls. Cardiomyopathy was defined according to standard functional and histological criteria. RESULTS Patients with dilated cardiomyopathy, either of alcoholic or hypertensive origin, showed increased myocardial superoxide dismutase activities compared with patients without cardiomyopathy (p < 0.001, both) and controls (p < 0.05, both). Total antioxidant status capacity and the activity of glutathione peroxidase and glutathione reductase enzymes were similar in all groups. Superoxide dismutase activity was related to the presence of cardiac enlargement and the degree of cardiac histological damage. The amount and type of alcoholic beverages as well as the nutritional status of the patients were not related to myocardial antioxidant activity. CONCLUSIONS The presence of dilated cardiomyopathy, of either alcoholic or hypertensive origin, is related to an increase in myocardial superoxide dismutase activity.