Diverse patterns of unresponsiveness in an acetylcholine receptor-specific T-cell clone from a myasthenia gravis patient after engaging the T-cell receptor with three different ligands.

Using an acetylcholine receptor-specific T-cell clone (TCC) from a myasthenia gravis patient, we have compared the induction of unresponsiveness by three agents: an anti-V beta monoclonal antibody (mAb), complexes of MHC class II with specific peptide (DR4:peptide) and free peptide. Pretreatment with each agent without antigen-presenting cells specifically rendered the TCC unresponsive to a subsequent optimal stimulus. A substantial proportion of the DR4:peptide pretreated cells underwent apoptosis and the remainder were profoundly unresponsive. Apoptosis was less prominent after pretreatment with free peptide and was not significant with anti-V beta mab; with both, the unresponsiveness was transient in the survivors. These diverse effects of engaging the T-cell receptor in the absence of costimulation suggest that these agents act via different mechanisms, and give insights to the potential for specific immunotherapy.

Generation of kinins in synovial fluid from patients with arthropathy.

An enzyme-linked immunosorbent assay method is described for the measurement of kinin formation in synovial fluid from patients with rheumatoid and osteoarthritis (RA and OA). Basal kinin concentrations were less than 6 ng/ml in synovial fluid collected in the presence of inhibitors of kinin forming (kininogenase) and kinin metabolising (kininase) enzymes. During incubation of synovial fluid in the presence of kininase inhibitors alone, kinins were produced rapidly over the first 10 min, but production ceased completely within 30 min due to inhibition of the endogenous kininogenases; the rate of kinin generation during the early rapid phase correlated well with the plateau kinin concentration. Plateau kinin levels in synovial fluid from 15 patients with OA and RA ranged from 98 to 427 ng/ml, with a median value of 148 ng/ml. This study demonstrates clearly that synovial fluid from arthritis patients has the capacity to produce kinins. Although the number of patients was small, the amount of kinin generated in vitro varied over a wide range and a relationship between intra-articular kinin formation and clinical features may become apparent in a larger group of patients. The technique could also be used to investigate other biological systems in which a role has been proposed for kinins.

Metabolism and characterisation of kinins and Hoe 140 (kinin antagonist) in the synovial fluid of patients with inflammatory joint diseases.

Methods have been optimised for the collection of synovial fluid and the chromatographic separation of individual kinins (bradykinin and kallidin) in the fluid by HPLC. In addition, the stability of the kinin antagonist, Hoe 140, in synovial fluid was compared with that of synthetic bradykinin. Although bradykinin was completely degraded after incubation for only 6 h in pooled synovial fluid obtained from patients with rheumatoid arthritis, Hoe 140 was stable for as long as 2 weeks under the same conditions. These studies will provide quantitative information regarding levels of kinins in inflamed joints and an insight into the therapeutic potential of kinin antagonists.

Measurement of coffee and caffeine intake: implications for epidemiologic research.

Reported associations between coffee or caffeine intake and benign breast disease, cancers, and cardiovascular diseases have generally been weak and inconsistent. The apparent discrepancies in these studies might be attributable to imprecision in the measurement of coffee and caffeine intake. A study of a random sample of 2,714 U.S. adults disclosed considerable misclassification of total caffeine intake and, to a lesser extent, coffee intake when the estimates were limited to only the number of cups of coffee consumed. Adjustment for the following factors is recommended: amount of caffeinated and decaffeinated coffee consumed both on weekdays and on weekends; the size of the container used; the method used to brew caffeinated coffee; and the amount of caffeine imbibed from tea and soft drinks. Intake of coffee varied markedly between seasons of the year and over time. Random misclassification of coffee and caffeine intake would have the effect of obscuring dose-response relationships to disease incidence.

Confounders contributing to the reported associations of coffee or caffeine with disease.

The role of caffeine or coffee in causing or promoting the incidence of serious disease is equivocal. Two design factors may account for the discrepancies in reported findings on the effects of coffee drinking: (a) imprecision of measurement and (b) confounding variables. A study of 2,714 white U.S. adults disclosed that, of 32 risk factors analyzed by linear and logistic regression, only sex and cigarette smoking were found to be important potential confounders of caffeine and coffee intake. Partial R2 values of the other 30 risk factors were relatively small and were inconsistent for each sex. It is unlikely that any of these factors could explain any of the reported associations between caffeine or coffee consumption and certain diseases. However, certain weak associations with caffeine or coffee intake should be included in the study design when they are known to be risk factors of a disease under investigation. These factors for men are dietary fat intake, vitamin C intake, and body mass index; and for women are vitamin use, alcohol intake, stress, and perceived health status.

Plasma progesterone concentration in women with and without adenocarcinoma of the endometrium.

In the search for the postulated but elusive "estrogenic bias" in patients developing endometrial cancer, several authors have suggested lack of progesterone as the common denominator. In this study 21 patients at the time of diagnosis of Stage I disease are compared to stringently matched healthy control subjects. No significant difference was found in plasma progesterone concentrations between the two groups. These results, in conjunction with other calculated estrogenic indices based on these patients, provide no evidence of lack of progesterone at the onset of clinical disease. However, the effects of long-term progesterone lack related to chronic anovulation are not excluded by these findings.

Transfer before delivery on Merseyside: an analysis of the first 140 patients.

Pregnant women (140) were transferred to the Regional Unit between May 1979 and December 1981 for delivery of preterm infants considered to be at risk. The 144 live infants and seven stillbirths that were delivered had a mean birthweight of 1.37 kg and a mean gestation of 29 weeks; there were nine abortions. In 1980 the uncorrected neonatal survival for very low birthweight infants was significantly better for those transferred before delivery (81%) than for infants born in the Region and not transferred (52%). The survival of very low birthweight infants transferred after delivery was 53%.