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To determine the effect of dexamethasone on the antimyeloma effects of lenalidomide, we tested in vitro proliferation, tumor suppressor gene expression, caspase activity, cell cycling, and apoptosis levels in a series of multiple myeloma (MM) and plasma cell leukemia cell lines treated with lenalidomide and dexamethasone, alone or in combination. The effect of dexamethasone on the immunomodulatory activities of lenalidomide such as T cell and natural killer (NK) cell activation was measured via interleukin [IL]-2 production, and interferon- and granzyme B production respectively. Lenalidomide inhibited proliferation in most cell lines tested, and this effect was enhanced by dexamethasone. This effect was observed in MM cells containing the high-risk cytogenetic abnormalities t(4;14), t(14;16), del17p, del13, and hypodiploidy. Mechanistically, lenalidomide plus dexamethasone synergistically induced expression of the tumor suppressor genes Egr1, Egr2, Egr3, p15, p21, and p27 in MM cell lines and MM patient cells. The combination activated caspases 3, 8, and 9 and induced cell cycle arrest and apoptosis. Lenalidomide alone increased T cell production of IL-2, and NK cell production of interferon- and granzyme B. Notably, dexamethasone antagonized these immunostimulatory effects of lenalidomide in a dose-dependent manner. These data further elucidate the mechanism of action of lenalidomide and dexamethasone in MM, and suggest that use of low-dose dexamethasone with lenalidomide may retain the antiproliferative effect of lenalidomide while permitting greater immunomodulatory effects of this combination regimen.

THE threat to stratospheric ozone from supersonic transport (SST) exhaust emissions has been a subject of controversy since Hampson1first suggested that significant ozone reductions might be caused by discharged water vapour. Later, after Johnston2and Crutzen3pointed out that even larger ozone depletions might result from emitted nitrogen oxides, water vapour effects were considered to be relatively unimportant. In the intervening years, predictions of SST ozone modification have evolved with advancing scientific knowledge4–7. Using a recently revised model of the stratosphere8, we report here that a substantial ozone layer enhancement could accompany worldwide SST fleet operations, and that water vapour may be an important factor in SST assessments. We have also found that increased nitrogen fertiliser use might, likewise, enhance the ozone layer, in contrast with previous calculations of ozone reduction9–11.

THE recent measurements1–3of large values (8.1 ± 1.5 and (8.2 ± 2.7 × 10−12cm3s−1) of the rate coefficient for the reaction NO + HO2→ NO2+ OH (1) have led to some important revisions in our understanding of stratospheric photochemistry4. In particular, the predicted ozone perturbations due to the injection of nitrogen oxides by supersonic transport aircraft have become net ozone gains instead of losses5, while the predicted ozone depletion due to ozone-active chlorine from chlorofluoromethanes has almost doubled4. An unfavourable result of the adoption of the larger value of the rate coefficient for reaction (1) has been the prediction of excessive amounts of stratospheric ozone (10–20% more than the measured concentrations) both in terms of the total column abundance and the concentration profile at altitudes below 40 km. Attempts to remedy this discrepancy between theory and observation by altering the simulated lower stratosphere transport and by increasing the assumed amount of ozone-active chlorine were not successful. It is the purpose of this letter, however, to show that another recent measurement by Zahniser and Howard6of the rate coefficient, k2, for the reaction HO2+ O3→ OH + 2O2(2) largely resolves these problems of excessive stratospheric ozone in models. Zahniser and Howard have reported the first direct measurement of the reaction between HO2and ozone (reaction 2). Their temperature-dependent rate coefficient is k2= (1.4 ± 0.4) × 10−14exp [−(580 ± 100)/T] cm3s−1which at stratospheric temperatures is 4 to 5 times larger than the value recommended in the report of the NASA Chlorofluoromethane (CFM) Workshop4, that is, 7.3 × 10−14exp (−1,275/T) cm3s−1.

Substantial increases in atmospheric nitrous oxide (N2O) resulting from increased use of nitrogen fertilisers might cause large (to 10%; ref. 1) and unacceptable decreases in the stratospheric ozone content1–3. Such ozone decreases would be caused by catalytic reaction cycles involving odd-nitrogen (NOx≡ NO + NO2) which is formed by N2O decomposition in the upper stratosphere1. However, Turco et al.4, using a background chlorine level of 2 p.p.b.v. (parts per billion by volume), show that if the recently measured values of the reactions in Table 1 are used, a 50% increase in N2O would lead to a 2.7% increase in the stratospheric column density, although the ozone content above 30 km would be reduced by > 5% they also estimated (unpublished data) that the change in the ozone column density caused by doubling the N2O abundance would be very close to zero (within about 0.1%). Here we extend these calculations of N2O/ozone effects to two dimensions, thereby delineating the latitudinal dependence expected for such ozone perturbations; we also discuss the effects of changes in stratospheric chlorine levels (Clx≡ Cl + ClO + HCl) on predicted ozone changes.

Background: Carpal Tunnel Syndrome (CTS) is one of the most frequent cause of pain and paresthesias in the upper extremities. Neurophysiological studies allow to confirm diagnosis based on clinical evaluation.