Sulphanilic acid: divergent results in the guinea pig maximization test and the local lymph node assay

The guinea pig maximization test (GPMT) has proven to be a valuable tool for the identification of the skin sensitization potential of chemicals. The method identifies a hazard which can lead in the EC to compulsory labelling of that chemical. In the present study, data on sulphanilic acid derived from the GPMT has been compared with results from a second guinea pig assay (the cumulative contact enhancement test) and the murine local lymph node assay, both of which require only topical application of chemical. Except for the GPMT, no test identified any sensitizing activity associated with exposure to sulphanilic acid. These latter results are consistent with the experience gained from substantial human exposure in an occupational setting and from which no cases of allergic contact dermatitis to sulphanilic acid have arisen over a 20-year period. In consequence, it is questioned which test protocol in practice has given the more accurate identification of sensitization hazard relevant to man.     

Abnormalities of copper in Gilles de la Tourette syndrome

The Gilles de la Tourette syndrome is a disorder whose etiology and pathogenesis are little understood. The number of biochemical abnormalities described in this disorder is minimal. Ten of a total of 80 patients were found to have an abnormally low serum copper. A report is presented on two patients who consented to further detailed investigation and in whom copper radioisotope studies were carried out. Both exhibited abnormalities of copper handling, in that we observed an abnormally fast disappearance of copper from the plasma and an abnormally slow uptake by the liver. The rates of intestinal absorption and urinary excretion were normal. We did not identify an abnormal site of sequestration of the metal in the body.     

Fluid therapy for induced labour under epidural analgesia: biochemical consequences for mother and infant

Two types of fluid regimen were provided for patients having labour induced under epidural analgesia. Reasons for the infusion were to pre-load the circulation before the epidural, and subsequently to sustain maternal hydration. Both fluids were isotonic, one was predominantly saline based (Hartmann's solution) and the other contained both saline and dextrose. Blood glucose and serum sodium, lactate and beta-hydroxybutyrate were measured before the start of induction, at delivery and in the cord sample. Blood glucose and serum sodium were measured in the babies at 12 and 24 h of age. The dextrose-saline fluid caused small but significant changes in blood glucose and serum sodium which did not exceed the normal reference limits for either. The use of Hartmann's solution was associated with considerable rises in maternal serum beta-hydroxybutyrate at delivery. Neither fluid had any significant effect on the blood glucose or serum sodium in infants at 12 and 24 h of age.     

Perception of risk in women with a family history of breast cancer.

We present the findings of a pilot study to assess the perception of risk in 155 women with a family history of breast cancer by questionnaire. Only 11% of women were able to identify the correct population risk and more than half were unable to assess their own lifetime risk within 50% of the clinicians'' estimate. Although it is probable that women are helped by genetic counselling and if at substantial risk, annual mammography, the psychological impact of assigning true risk and the value of mammography need to be evaluated.     

Effects of alpha-adrenoceptor antagonists and clonidine on the haemodynamic response to acute hypovolaemia in conscious rabbits.

In conscious rabbits an inferior vena caval cuff was progressively inflated so cardiac output fell at a constant approximately 8% of its baseline value. There was a biphasic haemodynamic response, consisting of an initial compensatory phase during which there was progressive systemic vasoconstriction and tachycardia, followed by a decompensatory phase in which systemic vasoconstriction failed abruptly, blood pressure plummeted and heart rate declined. We tested the effects on the haemodynamic response of prior 4th ventricular, and in some cases intravenous, infusions of saline, yohimbine, clonidine, yohimbine plus clonidine, and bunazosin. From the results we conclude that a yohimbine-sensitive mechanism in the brainstem, possibly alpha 2-adrenoceptor-mediated, may be an essential element of the cardiac receptor-mediated decompensatory phase of acute central hypovolaemia, but does not contribute to the arterial baroreflex-mediated compensatory phase.     

Estimation of body composition in Chinese and British men by ultrasonographic assessment of segmental adipose tissue volume.

It has been shown that ultrasonographic measurements can be used to predict body composition in adults. The purpose of this study was to assess the relationship between ultrasonograph and caliper (SKF) measurements of subcutaneous adipose tissue thickness in athletic Caucasian (English, E) and Asian (Chinese, C) men against estimates of body composition determined from hydrodensitometry (HYD). The usefulness of a proposed ultrasonographic method of estimating lean and fat proportions in the upper and lower limbs was also evaluated as a potential method of predicting body composition. Ultrasonography (US) was used to measure adipose and skin thickness at the following sites: biceps, triceps, subscapular, suprailiac, abdominal, pectoral, thigh and calf. Caliper measurements were also made at the above sites. Subcutaneous fat thickness and segmental radius were measured directly from the display screen of the ultrasonic scanner (Aloka 500 SD). By applying the geometry of a cone, the proximal and distal radii of the upper arm and upper leg were used to calculate the proportionate volumes of adipose tissue. The best correlations for US and SKF were obtained at the quadriceps, subscapular and pectoral sites for E (r = 0.96, 0.93 and 0.90, respectively) and at the quadriceps, calf and abdominal sites for C (r = 0.90, 0.81 and 0.75, respectively). The best ultrasonographic predictor of the percentage fat in both groups was the percentage adipose tissue volume in the upper leg (r = 0.83 and 0.79 for C and E, respectively). Stepwise multiple regression analysis indicated that the prediction of percentage fat was improved by the addition of the ultrasonographic abdomen measurement in both groups: Chinese sample: %fat = %fat(leg) (0.491) + US abdomen (0.337) + 0.95 ( R = 0.89, s.e.e. = 1.9%); English sample: %fat = %fat(leg) (0.435) + US abdomen (0.230) - 0.765 ( R = 0.80, s.e.e. = 3.6%). It is concluded that ultrasonographic measurements of subcutaneous adipose tissue and volumetric assessment of percentage adipose tissue in the thigh are useful estimates of body composition in athletic English and Chinese males.     

TRACP Influences Th1 pathways by affecting dendritic cell function.

TRACP, a marker of osteoclasts, is also expressed by cells of the immune system. We identified a novel function for TRACP in the dendritic cell. DCs from TRACP knockout mice have impaired maturation and trigger reduced Th1 responses in vivo. We postulate that TRACP has an important role in the presentation of antigens to T cells. INTRODUCTION: TRACP is highly expressed by osteoclasts, activated macrophages, and dendritic cells (DCs). Knockout mice lacking TRACP have an intrinsic defect in osteoclastic resorption and macrophages that display abnormal immunomodulatory responses and cytokine secretion profiles. Our aim in this study was to investigate the significance of TRACP in the inductive phase of the immune response by examining dendritic cells from TRACP(-/-) mice. MATERIALS AND METHODS: Maturational state and function of leukocyte subsets in mice was assessed by flow cytometry. The ability of the immune system to respond to nonspecific activation and to specific antigen was assessed by delayed type hypersensitivity and the presence of isotype-specific serum antibody in vivo and T-cell proliferation and cytokine production in vitro. RESULTS: The ability of lipopolysaccharide (LPS) to upregulate MHC II and CD80 in DCs from TRACP(-/-) mice was reduced compared with wildtype mice, although production of IL-10 by DCs from TRACP-deficient animals was increased. T- and B-cell responses not involving antigen presentation (anti-CD3, TNP-ficoll) were normal in TRACP(-/-) mice, but responses to T-dependent antigens were impaired. Specifically, TRACP(-/-) mice had defective delayed hypersensitivity responses to picryl chloride and reduced proliferative responses to ovalbumin compared with wildtype mice. In response to ovalbumin, but not anti-CD3, T cells from TRACP(-/-) mice produced less interferon-gamma (IFN-gamma), but there was no difference in IL-4 production: TRACP(-/-) mice also produced less ovalbumin (OVA)-specific IgG2a after immunization. CONCLUSIONS: The finding that DCs from TRACP(-/-) mice have impaired maturation and defective Th1 responses shows that TRACP is important for polarizing responses in na?ve T cells to antigen-presented dendritic cells.     

Intrinsic activity determinations at the dopamine D2 guanine nucleotide-binding protein-coupled receptor: utilization of receptor state binding affinities.

Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity agonist (HiAg) and a low affinity agonist (LowAg) state. The formation of the HiAg state is promoted by agonists, and the formation of this state of the receptor appears to be a critical factor in the generation of the effector-activating complex G alpha.GTP.Mg2+ and in the production of a stimulus. The magnitude of the difference in the affinity a compound has for the HiAg versus the LowAg state of the receptor has been related to the intrinsic activity of the compound. In this paper the HiAg and LowAg affinities (Ki) of full and partial dopamine agonists of varying levels of intrinsic activity were determined using membranes from Chinese hamster ovary cells stably transfected with the D2i receptor. The HiAg state was defined using the recently described dopamine agonist ligand [3H]U-86170, and the LowAg state was defined using [3H] raclopride plus 600 microM GTP. The LowAg/HiAg ratios for apomorphine (43), HW-165 (12.5), (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(-)-3-PPP] (4.5), terguride (1.6), SDZ-208-911 (1.2), and SDZ-208-912 (0.3) were found to correlate well with their electrophysiologically derived intrinsic activities (r = 0.92). Using this relationship, the intrinsic activity for compounds such as (+)-3-PPP (112%), quinpirole (104%), U-68553B (102%), and U-86170 (95%) was predicted to be high (greater than 90%); (-)-apomorphine (73%) was of high/moderate intrinsic activity, HW-165 (52%), (+)-apomorphine (51%), and (-)-3-PPP (34%) were in the intermediate range, and terguride (16.5%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were at the lower end of the intrinsic activity spectrum. The receptor state binding-determined intrinsic activity values for quinpirole (100%), U-86170F (94.8%), HW-165 (52.1%), (-)-3-PPP (34.3%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were found to correlate well (r = 0.908) with their maximum response (intrinsic activity), as determined using ATP-mediated increases in arachidonic acid release from CHO-D2i cells. In addition, the maximal effect of several of these compounds on rat striatal homovanillic acid (HVA) levels was determined. The drug-induced changes in tissue HVA levels were found to be consistent with the affinity-derived intrinsic activities of the drugs.(ABSTRACT TRUNCATED AT 400 WORDS)