Inhibitory action of mibefradil on calcium signaling and aldosterone synthesis in bovine adrenal glomerulosa cells

Mibefradil is a new cardiovascular drug with peculiar Ca++ antagonistic properties. The most remarkable feature of mibefradil is its unique relative selectivity for T type calcium channels, a property that has been proposed to explain in part the beneficial pharmacological and clinical profiles of this drug. In adrenal glomerulosa cells, aldosterone biosynthesis and secretion in response to angiotensin II or extracellular potassium is dependent on a sustained influx of Ca++ through T type Ca++ channels. The effect of mibefradil on the steroidogenic function of glomerulosa cells was therefore investigated. Using the patch clamp technique, we found that mibefradil inhibits selectively and in a concentration-dependent manner (IC50 = 3 microM)++ T type currents in bovine glomerulosa cells. In addition to this tonic (voltage independent) inhibition, the drug also induced a shift of the steady-state inactivation curve of these channels toward hyperpolarized voltages, contributing to its efficacy to prevent Ca++ influx into the cell through T type channels. Concomitantly, mibefradil reduced the cytosolic calcium responses to potassium and angiotensin II (as assessed with fluorescent probes), without affecting the capacitative Ca++ influx, and inhibited pregnenolone and aldosterone formation. This inhibition of steroidogenesis was not exclusively due to mibefradil action on voltage-operated Ca++ channels, because this agent also partially reduced steroid synthesis induced by adrenocorticotropic hormone or forskolin, two activators of the cyclic AMP pathway. In conclusion, mibefradil is highly effective in adrenal glomerulosa cells in reducing T type channel activity and aldosterone biosynthesis, two actions that should contribute to the beneficial effect of the drug in the treatment of hypertension.     

Treatment of uveitis with recombinant human interleukin-13

AIM: To evaluate the anti-inflammatory cytokine interleukin-13 (IL-13) for the treatment of uveitis. METHODS: Uveitis was induced in monkeys by immunisation with human retinal S-antigen. Starting at the onset of disease, the animals were treated with IL-13 at 25 micrograms/kg, or vehicle control, injected subcutaneously once a day for 28 days. Intraocular inflammation was scored by indirect ophthalmoscopy for a period of 56 days. Circulating leucocyte levels were monitored. RESULTS: Uveitis started unilaterally in all but one animal. IL-13 inhibited inflammation both in the eyes in which the disease was present when the treatment was initiated (p = 0.0001), and in the contralateral initially negative eyes (p = 0.0001). After cessation of therapy, there was a progressive increase of inflammation in the IL-13 treated group. However, the beneficial effect of IL-13 extended into the 4 week follow up period. IL-13 produced an increase in circulating polymorphonuclear neutrophils and a decrease in lymphocytes. CONCLUSION: Administration of IL-13 appears to be a promising modality of treatment for severe uveitis.     

The current and residual value of superphosphate,Christmas Island C-grade ore,and Calciphos as fertilizers for a subterranean clover pasture

The effectiveness in the year of application of three phosphorus fertilizers, superphosphate, Christmas Island C-grade ore, and 500°C calcined Christmas Island C-grade ore (Calciphos), was measured for 5 consecutive years in a field experiment on a lateritic soil. The residual value of the phosphorus fertilizers was also measured for 6 years. Dry matter production of subterranean clover-based pasture and bicarbonate extractable soil phosphorus were used as indicators of fertilizer effectiveness.Despite the use of very large amounts of C-grade ore and Calciphos, the plateau of the pasture yield versus fertilizer applied curve for these fertilizers did not reach the yield plateau achieved with superphosphate in either the short or long term.C-grade ore and Calciphos were 3% and 8% as effective as superphosphate for dry matter production in the year of application. Relative to superphosphate applied in the current year the effectiveness of superphosphate decreased by about 70% between the first and second year after application and decreased by a further 14% from year 3 to year 6. C-grade ore and Calciphos remained about 2% and 9% as effective as currently applied superphosphate each year.The residual value of superphosphate as measured by bicarbonate-extracted soil phosphorus decreased by about 60% from year 2 to year 7. The residual value of Calciphos was very low for year 2, doubled from year 2–4 and thereafter decreased gradually to its original value by year 7. The residual value of C-grade ore was extremely low throughout the experiment. Thus after year 2, compared to pasture yield, bicarbonate extracted soil phosphorus overestimated the residual value of superphosphate and calciphos.It follows that neither C-grade ore or Calciphos are suitable replacement fertilizers for superphosphate for use on pastures growing on lateritic soils in south-western Australia.     

Langerhans' cell histiocytosis and juvenile xanthogranuloma of the orbit. Clinicopathologic, CT, and MR imaging features

The clinical, radiologic, and histopathologic features of two main disorders of the orbit are discussed. Group I, Langerhans cell histiocytosis (histiocytosis X, Class I), is caused by proliferation of X histiocytic Langerhans' cells. Group II is juvenile xanthogranuloma, and Class II is related to the proliferation of non-X histiocytic (monocyte-macrophage) cells. The two diseases are of unknown cause and differ in their clinical, radiologic, and histopathologic features.     

The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor

Tyk2 belongs to the Janus kinase (JAK) family of receptor associated tyrosine kinases, characterized by a large N-terminal region, a kinase-like domain and a tyrosine kinase domain. It was previously shown that Tyk2 contributes to interferon-alpha (IFN-alpha) signaling not only catalytically, but also as an essential intracellular component of the receptor complex, being required for high affinity binding of IFN-alpha. For this function the tyrosine kinase domain was found to be dispensable. Here, it is shown that mutant cells lacking Tyk2 have significantly reduced IFN-alpha receptor 1 (IFNAR1) protein level, whereas the mRNA level is unaltered. Expression of the N-terminal region of Tyk2 in these cells reconstituted wild-type IFNAR1 level, but did not restore the binding activity of the receptor. Studies of mutant Tyk2 forms deleted at the N terminus indicated that the integrity of the N-terminal region is required to sustain IFNAR1. These studies also showed that the N-terminal region does not directly modulate the basal autophosphorylation activity of Tyk2, but it is required for efficient in vitro IFNAR1 phosphorylation and for rendering the enzyme activatable by IFN-alpha. Overall, these results indicate that distinct Tyk2 domains provide different functions to the receptor complex: the N-terminal region sustains IFNAR1 level, whereas the kinase-like domain provides a function toward high affinity ligand binding.