Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus

A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.     

Fecal occult blood screening in the Minnesota study: role of chance detection of lesions

BACKGROUND: In the Minnesota Colon Cancer Control Study, annual fecal occult blood testing reduced mortality from colorectal cancer by at least 33.4%. Some attribute a large part of this reduction to chance detection of cancers by colonoscopies; rehydration of guaiac test slides greatly increased positivity and consequently the number of colonoscopies performed. This study was conducted to determine how much of the reduction resulted from chance detection. METHODS: We used a mathematical model developed by Lang and Ransohoff to estimate the proportion of the 33.4% mortality attainable by chance alone. Applying the model requires the specification of five parameters: duration of follow-up, rate of compliance with fecal occult blood testing, rate of compliance with colonoscopy, positivity rate, and efficacy of colonoscopy in reducing colorectal cancer mortality. We took values for four of the five parameters directly from the Minnesota study. For the fifth parameter, efficacy of colonoscopy, we selected a value of 60%, based on the conclusions of another study. Whereas the Lang-Ransohoff model selects persons for colonoscopy by chance alone, those with bleeding cancers would also be selected by sensitive fecal occult blood testing. We therefore adjusted the result of the Lang-Ransohoff model for this dual detectability. RESULTS: We found that 16%-25% of the reduction in colorectal cancer deaths effected by fecal occult blood testing in the Minnesota study was due to chance detection; the remainder was due to sensitive detection. CONCLUSION: Chance played a minor role in the detection of colorectal cancers by fecal occult blood testing in the Minnesota study.     

ERCP and CT findings of ectopic drainage of the common bile duct into the duodenal bulb

OBJECTIVE: The purpose of this study was to evaluate ERCP and CT findings of ectopic drainage of the common bile duct into the duodenal bulb. CONCLUSION: Although rare, the diagnosis of ectopic drainage of the common bile duct into the duodenal bulb is important to prevent inadvertent damage during biliary tract or gastric surgery and to clarify the cause of chronic peptic ulcers.     

Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional control of advanced, resectable head and neck cancers: RTOG 88-24

PURPOSE: Despite aggressive surgery and postoperative radiation therapy, only 30% of patients who have advanced, potentially resectable carcinomas of the head and neck survive for 5 years. In the hope of improving this situation we studied the effect of postoperative radiotherapy delivered concurrently with cisplatin. METHODS AND MATERIALS: Patients who had Stage IV tumors and/or involved surgical margins received 60 Gy in 30 fractions over 6 weeks plus 100 mg/m2 of cisplatin on radiotherapy days 1, 23 and 43. Fifty-two patients participated in this trial and 51 were evaluated. Forty-three (84%) patients had pathologic T3 or T4 disease, 43 (84%) had Stage IV disease, and 27 (53%) had histologically involved surgical margins. RESULTS: Severe and life-threatening toxicities occurred in 20% and 12% of patients, respectively; the most common drug-related toxicities were leukopenia, anemia, nausea, and vomiting. Seventeen patients (43%) remain alive with no evidence of disease. Four patients (8%) died with no evidence of neoplastic disease, and one patient has died of a second independent malignancy. By actuarial analysis at 3 years, 48% of patients are alive, 81% have locoregional control of disease, and 57% are free of distant metastases. CONCLUSIONS: Based on comparison with similar patients treated in a prior Radiation Therapy Oncology Group/Intergroup trial (RTOG), we conclude that postoperative radiotherapy with concurrent cisplatin may improve locoregional control rates and should be prospectively tested.     

Should the same glucose values be targeted for type 1 as for type 2 diabetics in pregnancy?

OBJECTIVE: Our purpose was to determine whether the same maternal glycemic control is necessary to achieve similar perinatal outcomes for type 1 as for type 2 diabetics. STUDY DESIGN: The subjects were all women with pregestational diabetes mellitus delivered of live-born singletons. Glycemic control was achieved with diet and insulin. Self-monitoring of blood glucose was performed before meals and at bedtime. Target glucose values were 60 to 90 mg/dl fasting and 60 to 105 mg/dl at other times. RESULTS: Of 60,628 deliveries, 46 type 1 and 113 type 2 diabetic women met inclusion criteria. Respective differences were found between type 1 and type 2 diabetics in average daily glucose levels (112 mg/dl vs 97 mg/dl, p < 0.001), percent of values within target ranges (35% vs 57%, p < 0.001), and mean amplitude of glycemic excursion (48.1 mg/dl vs 24.9 mg/dl, p < 0.001). At least one daily glucose value was < 50 mg/dl during 19% of observation days for type 1 vs 2% of observation days for type 2 pregnancies (p < 0.001). There were no statistically significant differences between type 1 and type 2 diabetic pregnancies in neonatal macrosomia (30% vs 34%), proportion of cesarean deliveries during labor for arrest disorders (67% vs 69%), shoulder dystocia (2% vs 6%), and neonatal hypoglycemia (18% vs 26%). CONCLUSIONS: Less stringent maternal glycemic control may permit comparable maternal and neonatal outcomes for type 1 compared with type 2 diabetics. Higher target values for type 1 diabetics may decrease the frequency of maternal hypoglycemic episodes.     

Examination of the relationship between African American adolescents' condom use at sexual onset and later sexual behavior: implications for condom distribution programs

School-based condom distribution programs have generated considerable controversy across the country. In the present study 249 sexually active African American adolescents who did (n = 119) and did not (n = 130) use a condom during their initial sexual experience were compared to assess whether condom use at the onset of sexual activity was associated with later differences in sexual behavior. The results indicated that youths who used a condom from the onset of sexual activity were more likely to have used a condom in the most recent intercourse occasion, less likely to be diagnosed with a sexually transmitted disease (STD) or to combine substance use with sexual activity, endorsed more positive attitudes toward condoms, and were older when they initiated sexual activity. The findings have implications for condom availability programs and indicate that initial condom use was not associated with earlier onset of sexual activity and was associated with higher rates of precautionary behavior among sexually active minority adolescents.