Islet cell and insulin autoantibodies in subjects at high risk for development of Type 1 (insulin-dependent) diabetes mellitus: the Lyon family study

Summary Genetic determination as well as prospective analysis of islet cell autoantibodies and autoantibodies to insulin were conducted in a population of 479 first degree relatives of 174 Type 1 (insulin-dependent) diabetic patients. Analysis of HLA haplotypes within families illustrated the high frequency of DR3 and DR4 alleles with preferential transmission from parent to both affected and unaffected offspring. DR4 was preferentially associated with DQw3.2 (TA10^–) in 60/73 (82.2%) patients and 101/127 (79.5%) relatives. Relatives have been followed for a period of 800 subject-years. Twenty-two out of 430 relatives (5.1%) were found islet cell antibodies (ICA-IgG) positive. Seven sera with low titres became negative 6 months later at two different determinations. Fifteen sera ICA-IgG and ICA-protein A positive with high titres remained positive thereafter. Half of the ICA positive relatives were also found insulin autoantibodies (IAA) positive. All but 3 ICA negative relatives did not have IAA in their sera. Analysis of IAA specificity with competition experiments indicated that most antibodies recognised epitopes shared between human and pork insulins while four were specific for human insulin determinants. Analysis of class I and class II HLA antigen distribution indicated no particular allelic restriction in antibody positive individuals. Metabolic status of antibody positive relatives was determined with oral and intravenous charge of glucose. Two haplo-identical DR3-DQw2 brothers became diabetic during the study. One child and one mother both with DR4-DQw3.2 became intolerant to glucose. Each of these relatives had high titre ICA prior to metabolic deterioration. Taken together, these data indicated that ICA and IAA may be present in first degree relatives of diabetic patients. Individualisation of markers of the ongoing autoimmune process and accurate evaluation of the residual B-cell mass are necessary steps before further immune interventions in the early phases of the disease.     

Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea

Diarrhea is a significant problem in patients with acquired immunodeficiency syndrome (AIDS). The aim of this study was to determine octreotide effectiveness in refractory AIDS-associated diarrhea. In a 3-week protocol, 129 patients with a stool weight of >500 g/day despite standard antidiarrheal therapy were randomized to receive octreotide or placebo (3:2 ratio). Octreotide dose was increased 100 μg weekly to a maximum of 300 μg three times a day based on weekly 72-hour stool collections. Subsequently, patients received open-label octreotide at doses of up to 500 μg three times a day. A 30% decrease in stool weight defined response. After 3 weeks, 48% of octreotide- and 39% of placebo-treated patients had responded (P = 0.43). At 300 μg three times a day, 50% of octreotide- and 30.1% of placebo-treated patients responded (P = 0.12). At a baseline stool weight of 1000–2000 g/day, 57% of octreotide- and 25% of placebo-treated patients responded (P = 0.06). Response rates based on CD4 counts, diarrhea duration, body weight, human immunodeficiency virus risk factor, and presence or absence of pathogens showed no benefit of octreotide. Adverse events were more frequent in the octreotide-treated group. In the doses studied, octreotide was not more effective than placebo in patients with refractory AIDS-associated diarrhea. This lack of effectiveness may be attributable to inadequate sample size, doses, and duration of study treatment.     

Lack of evidence for hepatitis B virus (HBV) infection in fulminant non-A,non-B hepatitis

We studied eight patients who had orthotopic liver transplantation for fulminant hepatic failure in the course of acute non-A, non-B hepatitis. HBV DNA was searched for extensively in the liver tissue by PCR using several sets of primers in conventional and heminested reactions. All patients were negative for HBV DNA in liver tissue by all assays employed; furthermore, they were negative for HEV RNA, HCV RNA, and HBV DNA in serum. Although the causative role of HEV and HCV in fulminant non-A, non-B hepatitis cannot be excluded, our data do not support a causative association between this syndrome and HBV infection.This study was supported by Grant CR20 from the Mayo Clinic and Foundation. D.H.P. is supported by Public Health Service grants AI 32403, AR 41497, and AI 30548 from the National Institutes of Health.     

Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized double-blind study controlled with placebo

Backgrounds/Aims: Intense pruritus and the risk of stillbirths and premature deliveries justify the search for an effective pharmacologic treatment of intrahepatic cholestasis of pregnancy. This study was designed to test the efficacy of ursodeoxycholic acid in maternal pruritus, the biochemical abnormalities and the outcome of pregnancy, in patients with intrahepatic cholestasis of pregnancy of early onset.Methods: Pregnant patients hospitalized in a secondary case-referral center with intense pruritus and abnormal serum levels of bile salts and aminotransferases, detected before week 33 of pregnancy, were randomly assigned to receive ursodeoxycholic acid, 1 g per day orally, or an identical placebo, until delivery, in a double-blind study. A 3-week trial period was chosen to compare drug and placebo effects. The follow-up was extended for 3 months after delivery.Results: Twenty-four patients entered the trial; eight had deliveries before 2 weeks of treatment and one dropped out. The study was then completed in 15 patients: eight received ursodeoxycholic acid and seven placebo. No adverse effects were detected in the mother or in their babies. After 3 week of treatment, patients receiving ursodeoxycholic acid (mean daily) dose 16 mg/kg body weight) had a significant improvement in pruritus (p<0.02), In serum bilirubin (0.36±0.19 mg/dl (mean±SD) versus 0.95±0.48 in patients receiving placebo, p<0.01), in aspartate aminostransferase (52±42 IU/l vs 98±44, p<0.05) and in alanine aminotransferase (54±50 IU/l vs 229±154, p<0.01); serum total bile salts also tended to be lower in patients receiving ursodeoxycholic acid (26.3±33.7 μmol/l vs 55.0±44.8, p N.S.). Deliveries occurred at or near term in all mothers who received ursodeoxycholic acid (mean week of pregnancy: 38), while they occurred before week 36 of pregnancy in five patients who received placebo, including one stillbirth. All babies born alive had birth weights adequate for gestational age and they were thriving normally 3 months after delivery.Conclusions: Ursodeoxycholic acid is effective and safe in patients with intrahepatic cholestasis of pregnancy of early onset, attenuating pruritus and correcting some biochemical abnormalities in the mothers. Relevant aspects of fetal outcome were also improved in patients receiving ursodeoxycholic acid compared to placebo.     

Flow cytometric DNA ploidy and S-phase fraction correlate with histopathologic indicators of tumor behavior in colorectal carcinoma

BACKGROUND: The clinical behavior of colorectal carcinoma is highly variable without reliable predictive biomarkers. Previous reports have shown that flow cytometric DNA analysis may provide valuable prognostic information in these tumors. PURPOSE AND METHODS: This study evaluates the DNA ploidy and the S-phase fraction (SPF) on frozen samples obtained from 61 patients with colorectal carcinoma by using flow cytometry, and it correlates the data with histopathologic features known to affect disease prognosis. Tumors were classified using the World Health Organization's histologic criteria and were staged according the American Joint Committee on Cancer's classification system. Grade of the neoplasm, vascular invasion, and perineural tumor spread were evaluated in every case. RESULTS: Fifty-nine percent of tumors were aneuploid and showed statistically significant higher S-phase values than diploid tumors (22.5 vs. 11.2 percent; P < 0.00001). Mean SPF of the whole series was 17.9 (range, 4.2–44.2) percent. A statistically significant association was found between SPF values and histologic grade (P < 0.0016), nodal status (P <0.0007), distant metastasis(P < 0.0001), tumor stage (P <0.0001), venous invasion (P < 0.0002), and lymphatic permeation (P < 0.01) but not with perineural growth and infiltration of the neoplasm through the bowel wall (T). DNA ploidy correlated positively with tumor stage (P <0.03), and the association between aneuploidy and advanced stages of the disease was statistically significant. CONCLUSIONS: These findings showed that flow cytometric DNA ploidy and SPF, evaluated in fresh samples, are potentially useful parameters to estimate colorectal carcinoma biopathology. Aneuploidy and high replicative neoplastic activity correlated with histopathologic features that are commonly associated with the prognosis of colorectal carcinoma, being SPF-related to disease dissemination and, therefore, an indicator of clinical relevance.     

Tiotidine,a new H2-receptor antagonist,is a potent inhibitor of nocturnal acid secretion in duodenal ulcer patients

The efficacy of tiotidine, a new H₂-receptor antagonist, in reducing nocturnal acid secretion of duodenal ulcer patients (N=12, ages 21–60 years) was investigated. Different doses of tiotidine, 25, 50, 100, and 150 mg or placebo, were given as a single oral dose and acid secretion collected overnight. Tiotidine produced a significant, prolonged, and dose-related reduction of the nocturnal acid secretion without important side effects. The inhibition of cumulative H⁺ secretion after 25, 50, 100, and 150 mg tiotidine was 80, 89, 96, and 98% of that observed after placebo, while 300 mg of cimetidine caused an 87% inhibition. Compared to cimetidine, tiotidine appears to be approximately eight times more potent on a molar basis than cimetidine as an inhibitor of acid secretion, and the tiotidine effect is more prolonged. This strong and safe H₂-receptor antagonist may be an important addition to the treatment of acid hypersecretory states.     

Carcinoid tumors of the gastrointestinal tract. Analysis of 21 cases

Twenty-one patients with carcinoid tumors have been analysed. Out of 18 patients the diagnostic was made at operation and out of 3 by autopsy. The most frequent sites of the primary tumors were the appendix (38.1%), ileum (23.8%) and colon (19.9%). Asymptomatic tumors were found incidentally in 10 patients (55.5%). The symptomatic neoplasms were more common in the ileum. No one patients in this series obtained the diagnostic of carcinoid tumors before operation or autopsy. It was not observed the malignant carcinoid syndrome. Sixteen patients (88.8%) were submitted to resection and the mean survival was 10.7 years. Two patients (11.1%) were submitted to palliative operations and the mean survival was 3.5 months. The incidence of metastases in cases with carcinoid greater than 2.0 cm in diameter was 71.4%; on the other hand, the patients with carcinoids 2.0 cm in diameter or smaller than this size disclosed metastases in 7.6%. No patients with appendix carcinoid showed metastases and all patients with metastases presented ileum or colon carcinoids. In this series, the prognostic was related with the lesion's size, the localization of the tumor in the gastrointestinal tract and with the resection or not of the primary neoplasm.     

Adenosine deaminase, 5′-nucleotidase,xanthine oxidase,superoxide dismutase,and catalase activities in gastric juices from patients with gastric cancer,ulcer, and atrophic gastritis

Adenosine deaminase (ADA), 5-Nucleotidase (5NT), Xanthine oxidase (XO), Cu-Zn Superoxide dismutase (SOD) and Catalase (CAT) activities were determined in gastric juices from patients with gastric cancer, ulcer, gastritis and from healthy subjects. Enzyme activities were given as units per ml gastric juice and units per mg protein in gastric juice. ADA, 5NT and XO activities were found lower and protein concentrations were found higher in the cancer group than controls. There was however no significant difference between Cu-Zn SOD activities of the cancer and control groups. In all groups including control one, we could not find catalase activities in most of the samples. On the other hand, ADA, 5NT activities and protein concentrations in the gastric juice were lower in the gastritis group than control group. In the ulcer group, we found higher Cu-Zn SOD and XO activities and lower 5NT activity and protein concentrations compared with control values. In an attempt to establish statistical correlations between mean enzyme activities, pH and protein concentrations in the gastric juices of the groups, we found noticeable intra and inter-correlations, which indicated possible relations between DNA and free radical metabolizing enzymes.     

Apoptosis of naive CD4+ T-cells from HIV-infected patients with poor immune response to HAART is enhanced in vitro by steroid

OBJECTIVE: Because the absence of immune restoration in HIV-infected patients efficiently treated by highly active antiretroviral therapy (HAART) may be due to excessive immune activation, we prospectively studied the effect of hydrocortisone on T-cell apoptosis in a cohort of patients with satisfactory virologic response. METHODS: Apoptosis of T-cell subsets including na?ve CD45RA(+)CD4+ T-cells was determined at baseline and at months 1 and 3 after initiation of HAART. A satisfactory immune response was defined as an increase >100/microL CD4+ T-cells at month 3 compared to baseline. RESULTS: Twenty out of 63 patients showed undetectable viral load at month 3, among whom eight exhibited a satisfactory immune response. Down-regulation spontaneous CD4+T-cell apoptosis was significant in the group of patients with a satisfactory immune response compared to the other patients. However, hydrocortisone up-regulated apoptosis of na?ve CD4+ CD45RA+ T-cells, specifically in group of patients with poor immune response, whatever the time point considered: percentage of apoptotic CD4 T-cells was 16+/-16% without hydrocortisone and 22+/-22% with hydrocortisone at month 1, and respectively, 10+/-9 and 17+/-15% at month 3 (P < 0.05) Hydrocortisone had no impact on CD8+ T-cell apoptosis, whatever the considered group. CONCLUSION: Our results suggest to not use steroid therapy as adjuvant immunotherapy in patients with less than optimal immunologic response to HAART.