The high affinity state of inositol 1,4,5-trisphosphate receptor is a functional state

Inositol 1,4,5-trisphosphate (InsP3) is a second messenger responsible for the rapid and discontinuous release of Ca2+ from intracellular stores. In this study, the effects of the sulfhydryl reagent thimerosal were investigated on Ca2+ mobilization and on InsP3 binding. Thimerosal was shown to release Ca2+, in a dose-dependent manner, with an EC50 of 135.8 +/- 5.2 microM, from bovine adrenal cortex microsomes. Thimerosal-induced Ca2+ release was not prevented by heparin (250 micrograms/ml), ruling out a participation of InsP3 receptor in that effect. The slow rate of thimerosal-induced Ca2+ release rather suggested an inhibition of microsomal Ca2+ ATPase. At submaximal concentration, thimerosal (100 microM) was also shown to potentiate the release of Ca2+ induced by InsP3. Dose-response experiments revealed that thimerosal enhanced the apparent affinity of InsP3 by a factor 2.21 +/- 0.28, without modifying the maximal amount of Ca2+ released by InsP3. Thimerosal also enhanced, in a dose-dependent manner, [3H]InsP3 binding to adrenal cortex microsomes (EC50 = 43.3 +/- 7.6 microM). A similar effect was also observed on [3H]InsP3 binding to solubilized receptors, suggesting a direct modification of the receptor protein by thimerosal. The effects of thimerosal on Ca2+ release and [3H]InsP3 binding were abolished in the presence of the reducing agent dithiothreitol (1 mM), suggesting a modification by thimerosal of specific thiol groups on these microsomal proteins. Scatchard analysis revealed that thimerosal (100 microM) increased InsP3 receptor affinity by 1.87 +/- 0.26-fold. Kinetic analysis indicated that this increased affinity was due to an enhancement of InsP3 association rate constant. The concomitant increases of binding affinity and Ca2+ releasing potency suggest that the high affinity state of InsP3 receptor is a functional state.     

Neutrophil adhesion molecule expression during cardiopulmonary bypass with bubble and membrane oxygenators

The neutrophil-mediated tissue injury associated with cardiopulmonary bypass (CPB) is thought to require the interaction of specific neutrophil and endothelial adhesion molecules. In this study, the effects of CPB on the expression of neutrophil CD11b and CD18 (the components of the Mac-1 adhesion molecule) were examined; the effects of membrane versus bubble oxygenators on the expression of neutrophil CD11b and CD18 were compared; and the plasma levels of the intercellular adhesion molecule-1 (cICAM-1), an inducible endothelial adhesion molecule, were measured. In addition, the time courses of complement activation and neutrophil granule release were measured to determine their temporal relationship to the expression of the neutrophil adhesion molecule. Fifteen adult patients underwent procedures requiring cardiopulmonary bypass; hollow-fiber membrane oxygenators were used in 8 (group M) and bubble oxygenators were used in 7 (group B). Blood samples were drawn before, during, and after CPB for determination of the expression of neutrophil CD11b and CD18 (immunofluorescent flow cytometry), and the plasma cICAM-1, elastase, lactoferrin (enzyme-linked immunoabsorbent assay), and plasma C3a (radioimmunoassay) levels. CPB caused an immediate and sustained increase in the neutrophil CD11b and CD18 expression in both groups; after 60 minutes of CPB, CD11b expression had increased by 116.9% +/- 19.1% in group B and by 79.3% +/- 8.5% in group M (p = 0.78). Over the same period, CD18 expression increased by 97.2% +/- 17.9% in group B and by 72.4% +/- 16.8% in group M (p = 0.67).(ABSTRACT TRUNCATED AT 250 WORDS)     

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) disrupts social memory/recognition processes in the male mouse

Male mice treated with MPTP or vehicle were tested for their ability to demonstrate a memory-recognition response as evaluated in a habituation-dishabituation task. Treatment with MPTP severely disrupted the male's habituation-dishabituation response profile compared to vehicle treated animals. Administration of L-DOPA at 45 min prior to behavioral testing in MPTP animals restored their performance on the habituation-dishabituation test to levels observed in vehicle treated animals. There was also a tendency for L-DOPA to produce enhanced responsiveness in vehicle treated animals. Mice treated with MPTP had significantly reduced concentrations of norepinephrine within the olfactory bulb and hippocampus. Vehicle treated mice administered L-DOPA had significantly increased dopamine concentrations within the corpus striatum. These results suggest that, in addition to its putative effects upon the nigrostriatal dopaminergic system and motor behavior, MPTP is also exerting substantial effects upon other systems. In particular, the noradrenergic system and its potential involvement with memory/recognition processes in the CD-1 mouse appears to be very sensitive to the neurotoxic effects of MPTP.     

Massive lower gastrointestinal haemorrhage secondary to metastatic squamous cell carcinoma of the lung

Clinically significant symptoms due to gastrointestinal metastases from primary lung cancers is rare. A case of life-threatening lower gastrointestinal haemorrhage secondary to metastatic squamous cell carcinoma of the lung is reported. Previous reports of such metastases are reviewed, with reference to management and prognosis. After resection of colonic metastases from squamous cell lung cancer, survival is similar to that for primary disease. It is suggested that patients with known or suspected squamous cell lung cancer presenting with lower gastrointestinal symptoms be managed as aggressively as those with no previous history of disease.     

Teenagers' perceptions of barriers to prenatal care

A structured interview conducted during the postpartum hospitalization of 184 patients aged 17 years or younger was used to study teenagers' perceptions of barriers to prenatal care. The interview consisted of more than 100 questions on demographic characteristics, family and social support, desire for the pregnancy, perceptions of the importance of prenatal care, practical obstacles to access to health care (such as lack of transportation, day care, etc), financial problems related to care, problems finding time to obtain health care, knowledge of available prenatal care resources, and perceptions of ease or difficulty in the use of existing clinics. Multiple regression analysis using the Kessner index as the criterion variable showed that major factors related to the adequacy of prenatal care received by these teenagers were perceptions of cost barriers, the gestational age at which the teenager discovered she was pregnant, school enrollment status (those in school received poorer care than those who had dropped out), and the degree of social support experienced by the teenager. These findings suggest that specific changes in the health care system are needed to make prenatal care more accessible for pregnant teenagers. These changes would include enhancing community awareness that Medicaid pays for prenatal care, establishing links between prenatal clinics and school health systems, and scheduling prenatal clinics at times more convenient for teenagers.     

Comparison of six mammalian lysophospholipases

Lysophospholipases participate in the regulation of the levels of lysophospholipid, compounds with pleiotropic biological effects. Lysophospholipases were purified from a macrophage cell line (WEHI 265.1), a myelocytic leukemia cell line (HL-60) and peripheral blood eosinophils. WEHI 265.1 cells contain three lysophospholipases 28, 27 and 110 kDa as determined by polyacrylamide gel electrophoresis. The 110 kDa lysophospholipase also exhibits phospholipase A2 activity and appears to be identical to a previously described 110 kDa phospholipase A2. Similarly, the HL-60 cells have three lysophospholipases, the largest again a 110 kDa enzyme with phospholipase A2 activity and the smaller are 20 and 21 kDa. The low molecular mass lysophospholipases have distinctive chromatographic properties and amino acid compositions. However, the two low molecular mass enzymes from a given cell type are not radically different, e.g., 15 of the 20 amino acids of the C-terminal sequences of the HL-60 enzymes are identical. A single lysophospholipase, approx. 15 kDa, is a major eosinophil protein. This enzyme is different from those described above.     

Inhibition of melatonin secretion by ethanol in man

To determine whether ethanol inhibits nocturnal melatonin (MT) secretion, three experiments (A, B, and C) were performed in seven normal subjects. In A, ethanol at a dose of 0.34 g/kg was administered orally at 6:00, 8:00, and 10:00 PM. Each dose was increased to 0.52 g/kg in B. In C, water was substituted for ethanol. Blood samples for determination of serum MT levels were drawn every second hour between 6:00 PM and 8:00 AM. Urinary excretion of MT during the night was also determined. In A, serum ethanol reached a maximal level of 13 +/- 1 mmol/L at 12 midnight. In B, the corresponding maximum was 25 +/- 1 mmol/L. The higher alcohol dose inhibited nocturnal MT secretion by 20% +/- 5% (P < .01), whereas the lower dose lacked such effect. Urinary excretion of MT was left unaffected by alcohol at both doses. Five additional normal subjects were given alcohol as described above at a dose of 0.52 g/kg (experiment D). This induced mild nocturnal hypoglycemia as evidenced by a glucose decremental area (5.9 +/- 1.8 mmol/L.h) that differed significantly from zero (P < .05). To determine whether a reduced glucose delivery to pinealocytes might contribute to the decreased MT secretion in alcohol-intoxicated subjects, two experiments (E and F) were performed in eight healthy individuals. In E, ethanol was given orally as in B; three small oral doses of glucose were also given at 8:00 PM, 10:00 PM, and 12 midnight. In F, water was substituted for ethanol and glucose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cutanea tarda porphyria in 2 patients with kidney transplantation

In rheumatoid synovium interleukin 6 (IL-6) is the most abundantly expressed cytokine. Increased serum levels have been previously reported in patients with rheumatoid arthritis (RA). In this study serum IL-6 levels were measured in a well defined cohort using a bioassay (B9 cells) and levels were correlated with conventional clinical and laboratory indices of disease activity. Levels were significantly higher in serum from patients with RA (median 55 IU/ml; interquartile range 28-139) compared with serum from disease (median 7 IU/ml; 1-23) and normal controls (median 10 IU/ml; 7-12). No difference was observed between men and women. Levels did not correlate with disease duration. Significant associations were observed between IL-6 and C reactive protein and between the Ritchie articular index and duration of morning stiffness. No other correlations were observed. The value of these findings in the monitoring of RA and as an indicator of response to second line treatment needs to be established.