High seasonal variations of the radon exhalation from soil surface in the fault zones (Baikal and North Caucasus regions).

The seasonal variations of radon exhalation rate from soil surface were studied in two seismically active regions of the Russian Federation - the Baikal rift and the North Caucasus. In each region, monthly measurements of the radon exhalation have been carried out at two relatively proximal sites, one of which was located within the active fault zone and the other outside of the fault zone. The Open Charcoal Chamber Method was used. Very high radon exhalation rate values were found in the fault zones at both regions. At the Baikal rift, the radon exhalation reached 1.4 Bq m-2 s-1, and at the Caucasian region in some periods it even achieved 24 Bq m-2 s-1, which is an extremely high value. The same pattern of seasonal variations of radon levels with abnormal high radon exhalation rate values in summer and extremely low in winter were observed in both the Baikal and Caucasus regions. Clear correlation between radon exhalation and air temperature were also revealed. The obtained data and simulation results indicate that seasonal fluctuations in the radon exhalation rate are caused by the inversion of the direction of convective air flow in the fractured zones of the rock massif. In summer, the convective air flow is directed from the rock massif to the atmosphere and in winter, vice versa, from the atmosphere to the rock massif. This phenomenon is similar to the well-known "chimney effect", i. e. in winter there is a direct draft in the system of fractures, and in summer - the reverse one. Thus, the detected radon anomalies are due to near-surface convective air circulation in permeable zones of the mountain ranges and most probably are not associated with deep crustal or mantle degassing. Seasonal thermally induced radon anomalies should be taken into account both in the radon risk mapping and in the application of radon as a tracer of natural processes in various fields of geology and geophysics.

Effect of the 12-gene colon cancer assay results on adjuvant treatment recommendations in patients with stage II colon cancer.

INTRODUCTION: The 12-gene colon cancer Recurrence Score assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. A survey was performed characterizing the assay's impact on treatment recommendations for these patients. METHODS: US medical oncologists (n = 346) who ordered the assay for ≥3 stage II colon cancer patients were asked to complete a web-based survey regarding their most recent such patient. Physicians surveyed represented users of the assay within the first 2 years of commercial availability which may include 'early adopters'. RESULTS: Most of 116 eligible physicians were in community practice (86%), with median 14.5 years' experience (range = 2-40). Mean patient age was 61 years (range = 32-85); 81% had T3 disease, and 38% had comorbidities. Of 76 patients tested for mismatch-repair/microsatellite-instability (MMR/MSI), 13 (17%) were MMR-deficient/MSI-high; 46 (61%) MMR-proficient/MSI-low; and 17 (22%) unknown. Most patients (84%) had ≥12 nodes examined. Median Recurrence Score result was 20 (range = 1-77). Before assay, treatment recommendations were specified for 92 (79%) patients, with no recommendation for 24 (21%). Of the 92 with pre-assay recommendations, chemotherapy was planned for 52 (57%) and observation for 40 (43%); the assay changed recommendations for 27 (29%). Treatment intensity decreased for 18 (67%) and increased for nine (33%) patients; it was more likely to decrease for lower Recurrence Score values and increase for higher values (p < 0.001). CONCLUSION: For stage II colon cancer patients receiving Recurrence Score testing, 29% of treatment recommendations were changed. Use of the assay may lead to reductions in treatment intensity. Study limitations include retrospective design, data gathering during the first 2 years of assay availability only, and potential non-representativeness of respondents.

Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis.

OBJECTIVE: Morphine is a long-standing therapy in acute decompensated heart failure (ADHF), despite few supporting data. A study was undertaken to compare the outcomes of patients who did and did not receive morphine for ADHF. METHODS: The study was a retrospective analysis of the Acute Decompensated Heart Failure National Registry (ADHERE) which enrols hospitalised patients with treatment for, or a primary discharge diagnosis of, ADHF. Patients were stratified into cohorts based on whether or not they received intravenous morphine. ANOVA, Wilcoxon and chi(2) tests were used in univariate analysis, followed by multivariate analysis controlling for parameters previously associated with mortality. Analyses were repeated for ejection fraction subgroups and in patients not on mechanical ventilation. RESULTS: There were 147 362 hospitalisations in ADHERE at December 2004, 20 782 of whom (14.1%) received morphine and 126 580 (85.9%) did not. There were no clinically relevant differences between the groups in the initial age, heart rate, blood pressure, blood urea nitrogen, creatinine, haemoglobin, ejection fraction or atrial fibrillation. A higher prevalence of rest dyspnoea, congestion on chest radiography, rales and raised troponin occurred in the morphine group. Patients on morphine received more inotropes and vasodilators, were more likely to require mechanical ventilation (15.4% vs 2.8%), had a longer median hospitalisation (5.6 vs 4.2 days), more ICU admissions (38.7% vs 14.4%), and had greater mortality (13.0% vs 2.4%) (all p<0.001). Even after risk adjustment and exclusion of ventilated patients, morphine was an independent predictor of mortality (OR 4.84 (95% CI 4.52 to 5.18), p<0.001). CONCLUSIONS: Morphine is associated with increased adverse events in ADHF which includes a greater frequency of mechanical ventilation, prolonged hospitalisation, more ICU admissions and higher mortality.

Effect of acetaminophen on the accuracy of glucose measurements obtained with the GlucoWatch biographer.

BACKGROUND: Improved glycemic control significantly reduces long-term microvascular complications of diabetes mellitus associated with chronic hyperglycemia. The GlucoWatch biographer is designed to facilitate intensive diabetes management by providing automatic, frequent, and noninvasive glucose readings up to three times per hour for as long as 12 hours. METHODS: The device extracts glucose through intact skin using reverse iontophoresis and measures the extracted glucose with an electrochemical biosensor. A clinical trial was performed to assess the effect of acetaminophen, a potential interference for traditional blood glucose meters, on the accuracy of the GlucoWatch biographer in adult subjects with diabetes (n = 18). One thousand milligram doses of acetaminophen were administered to subjects in two groups: one to achieve Cmax (peak acetominophen concentration) at the time of biographer calibration and the other to achieve Cmax during the measurement period. The biographer readings were compared to serial fingerstick blood glucose measurements. RESULTS: Time profiles over 9 hours show close tracking of the biographer glucose results with fingerstick blood glucose measurements for all groups. The mean difference between the two measurements is between 8 and 12 mg/dL for all groups. The mean absolute value of the relative difference is less than 20%, and more than 93% of the points were in the clinically acceptable (A+B) region of the Clarke Error Grid. No statistically significant differences were found for any accuracy measurement across all groups. CONCLUSIONS: The GlucoWatch Biographer provides frequent measurements of glucose over a 12-hour period with high accuracy. No effect of therapeutic dosage of acetaminophen on the accuracy of the glucose readings was found.

IL-2 knockout recipient mice reject islet cell allografts.

The IL-2 pathway is portrayed often as central to allograft rejection. To test this hypothesis, we studied IL-2-deficient mice as allograft recipients. IL-2 gene knockout (KO) mice reject islet allografts and demonstrate a classical mononuclear leukocytic infiltrate, containing CD4+ and CD8+ T cells, surrounding and invading the islet allografts. Moreover, allograft rejection in the IL-2 KO mouse is associated with intragraft expression of certain cytokine and CTL attack molecule genes (e.g. IFN-gamma, IL-4, IL-7, IL-10, and granzyme B). In separate experiments, IL-2 KO mice generated CTLs in response to in vivo challenge with allogeneic tumor cells. Although IL-2 KO mice reject allografts in vivo, spleen cells from immunologically naive IL-2 KO mice exhibit a diminished proliferative response to mitogens in vitro that could be restored largely by exogenous IL-2, IL-4, or IL-7. The paradoxical ability to execute graft rejection in vivo despite near absent T cell proliferative responses in vitro may result from the expression of IL-7 in vivo, but not in vitro. Con A-stimulated bulk spleen cell cultures derived from IL-2 KO mice were essentially devoid not only of IL-2 but also IL-7 gene transcripts. These data indicate that 1) IL-2 is not the sole T cell growth factor capable of supporting allograft rejection and 2) expression of IL-4, but not IL-2, during the allograft response does not lead inevitably to tolerance.

5-Aminosalicylic acid abrogates T-cell proliferation by blocking interleukin-2 production in peripheral blood mononuclear cells.

The antiinflammatory agent sulfasalazine (SS) is prescribed to treat Crohn's disease, ulcerative colitis and rheumatoid arthritis. Activated T cells are present within diseased mucosal and synovial sites. We tested whether SS or its metabolites 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) inhibited the T-cell activation products interleukin 2 (IL-2) and interleukin 2 receptor alpha-chain (IL-2R alpha). Experiments were performed in phytohemaglutinin- and phorbol ester-stimulated peripheral blood mononuclear cells. Radioactive thymidine and leucine incorporation assayed DNA and protein synthesis, respectively. Enzyme-linked immunosorbent assay and Northern blot analysis measured IL-2 and IL-2R alpha. Lactate dehydrogenase release determined cell viability, and intracellular free calcium was measured by an indole fluorescent indicator. SS and 5-ASA, but not SP, inhibited T-cell proliferation and protein synthesis in phytohemaglutinin- and phorbol ester-stimulated peripheral blood monomuclear cells. 5-ASA (625 microM) markedly reduced culture supernatant IL-2 protein levels by 92% and steady-state IL-2 messenger RNA levels 4.4-fold at 24 and 18 hr, respectively. The supplementation of IL-2 restored T-cell proliferation only in 5-ASA-treated cultures. SS, 5-ASA and SP did not alter intracellular calcium accumulation after mitogenic stimulation. SS and 5-ASA (625 microM) caused 71% and 37% cytotoxicity, respectively, in 72-hr cultures. 5-ASA inhibits T-cell proliferation in part by blocking IL-2 messenger RNA accumulation and protein production downstream of the rise in cytosolic calcium. Inhibition of IL-2 production is an additional mechanism of action for 5-ASA.

An anergic, islet-infiltrating T-cell clone that suppresses murine diabetes secretes a factor that blocks interleukin 2/interleukin 4-dependent proliferation.

The mechanism of peripheral immunological tolerance has not been fully established. While anergic T cells have been noted in tolerant hosts, the mechanism by which they contribute to the induction and maintenance of tolerance has not been defined. As we previously reported, an accelerated form of diabetogenic autoimmunity in nonobese diabetic mice can be blocked by passive transfer of a CD3+, CD8+, beta-chain variable region 11-positive islet-infiltrating T-cell clone (IS-2.15). In this report we examine the properties of this T-cell clone. We have established that this clone is unresponsive to mitogenic concentrations of anti-T-cell receptor or anti-CD3 monoclonal antibodies and is only weakly responsive to syngeneic islet and spleen cells. Moreover, these T cells secrete an inhibitory factor(s) that irreversibly inhibits interleukin (IL) 2/IL-4-driven proliferation of IL-2/IL-4 indicator T-cell lines. This noncytotoxic factor, which possesses an apparent size of 10-30 kDa, does not interfere with low-affinity IL-2 receptor expression. These data indicate that at least some anergic T cells can play an active role in peripheral tolerance by secreting suppressor factor(s) that regulate IL-2/IL-4-dependent proliferation.

Interleukin 2 counteracts the inhibition of cytotoxic T lymphocytes by cholera toxin in vitro and in vivo.

Cholera toxin irreversibly activates a 43-kDa guanosine triphosphate (GTP)-binding protein by adenosine diphosphate ribosylation, resulting in activation of adenylate cyclase and increased intracellular levels of cyclic adenosine monophosphate (cAMP). Because increases in intracellular cAMP inhibit interleukin 2 (IL 2) expression and cytotoxic T lymphocyte (CTL) generation and function in vitro and in vivo, we hypothesized that IL 2 may counteract the inhibition of CTL by cholera toxin. Activated CTL treated with IL 2 were protected from the inhibitory effects of cholera toxin. IL 2 also counteracted the inhibitory effect of cholera toxin on steady-state levels of CTL-specific serine esterase mRNA. Given the putative role of serine esterase for in vitro generated CTL effector activity, these results may account for recovery of CTL activity. Although IL 2 restored CTL function and serine esterase transcription, it did not block cholera toxin-catalyzed ribosylation of the 43-kDa GTP-binding protein, nor did it prevent the accumulation of intracellular levels of cAMP. In vivo, C57BL/6 mice challenged with the allogeneic tumor P815 had suppressed CTL function when cholera toxin was administered. These cholera toxin-treated mice died of tumor overgrowth, whereas untreated mice rejected the allogeneic tumor. Co-treatment of alloimmunized mice with cholera toxin and IL 2 prevented death from tumor overgrowth and restored CTL function; 67% of these mice survived. These data provide evidence that IL 2 acts in CTL through a mechanism independent of cholera toxin-sensitive GTP-binding protein in vitro and in vivo, despite elevated intracellular cAMP levels.

Hypoglycemia due to antiinsulin receptor antibodies in systemic lupus erythematosus.

An elderly woman with unexplained episodic fasting hypoglycemia was hospitalized for ascites. Evaluation revealed polyserositis, arthritis and immunologic abnormalities that suggested the diagnosis of systemic lupus erythematosus (SLE). Antibodies to insulin receptor with insulin binding inhibitory activity were detected in her serum. Treatment with prednisone was accompanied by resolution of hypoglycemic episodes and disappearance of the antireceptor antibodies. Autoantibody mediated alterations in serum glucose may be included in the growing list of autoimmune phenomena in SLE. Antiinsulin receptor antibodies should be sought in patients with SLE and idiopathic hypoglycemia.

Antibody valence and induced signal transduction: the role of antibody valence in anti-CD3-induced signal transduction in isolated normal T cells.

This report provides direct evidence that protein kinase C (PKC) is activated in isolated, rigorously accessory cell (AC)-depleted T cells when the T cell antigen recognition complex is stimulated by divalent anti-CD3 monoclonal antibody. Anti-CD3 monoclonal antibody-stimulated PKC activation alone does not, however, directly stimulate T cell proliferation in the absence of AC. A rise in cytosolic calcium is the second signal believed to be of paramount importance in T cell activation. While mitogenic concentrations of some divalent anti-CD3 antibodies do not cause a rise in cytosolic calcium, polyvalent anti-CD3 does evoke increased intracellular Ca2+ in rigorously AC-depleted resting human T cells.

Similar effects of cyclosporine and verapamil on lymphokine, interleukin 2 receptor, and proto-oncogene expression.

Since calcium channel blocking agents and CsA exert an antiproliferative effect upon T cell mitogenesis, we have compared and characterized their immunosuppressive properties at the level of gene activation. Verapamil (greater than or equal to 30 microM), which blocks T cell mitogenesis and a rise in cytosolic calcium, was added to cultures of peripheral blood mononuclear cells stimulated with phytohemagglutinin (5 micrograms/ml) and phorbol myristate acetate (5 ng/ml). Northern blot analysis was performed using cDNA probes for the p55 interleukin 2 receptor (Tac; IL-2R), interleukin 2 and c-myc at 20 hr of culture. Accumulation of IL-2 encoding mRNA within the cytoplasm was completely abrogated by verapamil. However, IL-2R and c-myc encoding mRNA were clearly detectable in verapamil-treated cell cultures. Surface expression of the Tac protein in mitogen-activated T cells was also not blocked by verapamil as shown by FACS analysis. In companion experiments with CsA, verapamil only partially inhibits the intracellular processes leading to T cell activation. A calcium-independent pathway may exist for the expression of IL-2R and c-myc, while an increase of intracellular Ca2+ may provide the additional signal for IL-2 gene expression. Although the in vitro concentrations of verapamil used in these experiments are in excess of common clinically therapeutic levels, the results help clarify the mode of CsA action and may provide a new tool to dissect the early events of T cell activation.