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Search this Guide Search. Why Information Literacy? Rebecca Nowicki. Email Me. Contact: LA P. Library Hours. Have a requirement? Get Best Price. There are many reasons why Il Forno By Marco has become the leading manufacturer of wood fired ovens in India.

Some people say it is Marcos perfectionism and and professionalism that has given him his good reputation, others say it is the aesthetic appeal of his ovens. You can read more statements in our customer reviews.

In our factory we carve the bricks in the perfect shape to create the dome, and we bond them with fine refractory mortar.

The thickness and shape of our dome enables a strong thermal flywheel effect with consequent homogeneous and long-lasting heat. At those high temperatures you can cook a pizza in only minutes! Our wood fired ovens have a combination of multi-layer insulation that includes ceramic blankets, ceramic board and a concrete mix made out of aircreate to ensure the best heat retention.

The shape of the oven acts as a thermal battery retain the heat excellent. C Relationship between serum tocilizumab and CRP. The sensitivity of CRP assay in the present study was 0. Representative data are shown in the Figure 2 A. CRP is a representative acute-phase reactant, and change in CRP correlates with severity of inflammation. This shows that tocilizumab effectively inhibits IL-6 signaling when it is detectable in serum.

Serum IL-6 concentrations after a single dose of tocilizumab in healthy adult volunteers after the start of dosing once every 2 weeks in patients with RA, and in patients with Castleman disease were compared. In healthy volunteers, serum IL-6 showed a significant increase at day 7 after tocilizumab administration 3.

In patients with RA, serum IL-6 showed a greater increase at day 14 and had not changed at day 42 In patients with Castleman disease, serum IL-6 showed an even more significant increase at day 14, even though it was significantly lower in Castleman disease than in RA at baseline, and had not changed at day 42 Change in serum IL-6 after administration of tocilizumab.

Points and error bars show geometric means plus or minus SEs. Correlation between serum CRP at baseline and serum IL-6 at baseline or after tocilizumab administration. In order to know whether the IL-6R inhibition augmented the IL-6 production through the elimination of possible negative feedback by IL-6 on IL-6 production, changes in IL-6 mRNA expression after tocilizumab administration in peripheral blood cells were examined.

However, there was no significant difference in IL-6 mRNA expression at these 4 sampling time points, so administration of tocilizumab did not increase the production of IL-6 Figure 5. Bars and error bars show means plus SEs. The normalization of serum CRP, however, shows that IL-6 signaling was inhibited as long as free tocilizumab was detectable in serum. CRP is therefore a useful surrogate marker for tocilizumab levels that are high enough to inhibit the effects of IL-6 in patients.

This hypothesis is supported by the decrease in the C3, C4, and CH50 levels after tocilizumab administration that we observed in another study data not shown because complement factors are consumed during the elimination process of immune complexes. It is noteworthy that there was no difference between RA and Castleman disease with respect to serum sIL-6R either at baseline or after tocilizumab administration.

This suggests that there is no difference in sIL-6R production between these 2 diseases. For serum IL-6, on the other hand, the level after tocilizumab administration differed greatly between the diseases as well as between individual patients Figures 3 , 4.

This suggested to us that the degree of increase in serum IL-6 after inhibition of IL-6R by tocilizumab may reflect different levels of endogenous IL-6 production in these diseases and in individual patients. The serum IL-6 level depends on the balance between IL-6 production and elimination, so tocilizumab could potentially have caused serum IL-6 to increase either by stimulating production or by inhibiting elimination.

One possibility is that tocilizumab might stimulate the production of IL-6 if its blockade of IL-6 signaling inhibits a negative feedback effect of IL-6 on IL-6 production. This seems unlikely, however, because serum IL-6 did not continue to increase but remained steady between day 14 and day 42, and because there was no significant increase in IL-6 mRNA expression in peripheral blood cells after administration of tocilizumab.

The relevance of the latter observation may be limited, however, by the fact that we did not examine IL-6 mRNA expression in cells of the affected joints of patients with RA or the affected lymph nodes of patients with Castleman disease, which are important sources of IL-6 in these diseases. Another possible explanation for the increase in serum IL-6 after tocilizumab administration is that tocilizumab may inhibit the clearance of IL-6 from serum.

There are 2 possible elimination pathways of IL-6 from serum: one is receptor-mediated clearance via the binding of IL-6 to IL-6R; the other is direct degradation of IL-6 protein. The main elimination pathway may be receptor-mediated clearance. We would like to explain this mechanism of action with the help of the schematic bathtub model illustrated in Figure 6.

In this model, endogenous IL-6 production is represented by the stream of water flowing from the faucet into the tub at a constant rate that depends on the level of true disease activity.

Receptor-mediated IL-6 clearance is represented by water flowing out of the bathtub drain. Direct degradation of IL-6 is represented by minor water flowing out from the side small drain in this figure. When the bathtub drain is plugged, the water level will depend on the flow rate from the faucet. Likewise, when IL-6R is inhibited by tocilizumab, the serum IL-6 level will reflect the actual level of endogenous IL-6 production that correlates with the level of true disease activity while inflammatory symptoms are ameliorated by the inhibition of IL-6 signaling through IL-6R.

Schematic model of the mechanism by which serum IL-6 is increased when IL-6 receptor is blocked by tocilizumab. The bathtub model explains the elimination of IL-6 from serum before and after administration of tocilizumab. The rate of water flowing from the faucet into the tub the IL-6 production rate remains constant. Before tocilizumab administration, the rate of water flowing out of the bathtub the elimination of receptor-bound IL-6 from serum and IL-6 catabolism is also constant, so the water level serum IL-6 level remains constant.

The water level increases and then remains constant at a higher level serum IL-6 increases to a new steady-state level when the IL-6 production rate matches the IL-6 degradation rate. In practice, the correlation between CRP an indicator of resultant inflammation at baseline and serum IL-6 level after administration of tocilizumab was much closer than that between CRP at baseline and serum IL-6 level before tocilizumab administration. Furthermore, serum IL-6 was much higher in patients with Castleman disease than in patients with RA after tocilizumab administration, even though serum IL-6 in patients with Castleman disease was lower than that in patients with RA at baseline.

The difference in increased IL-6 level between RA and Castleman disease after tocilizumab treatment closely reflected the difference between RA and Castleman disease in baseline inflammatory activity and in laboratory abnormalities such as increased CRP and IgG values, whereas the IL-6 levels before tocilizumab treatment did not. The fact that IL-6 was lower in Castleman disease than in RA at baseline indicates that the elimination of serum IL-6 is much faster in Castleman disease than in RA without tocilizumab treatment, and the fact that this faster elimination in Castleman disease was greatly slowed by tocilizumab suggests that it is receptor-mediated elimination.

We conclude that the serum IL-6 level during inhibition of IL-6R by tocilizumab represents the actual endogenous production of IL-6 and the true disease activity of patients with different diseases much better than the serum IL-6 level before tocilizumab treatment. If the causal factors of IL-6 overproduction are neutralized by adequate therapy the faucet of the bathtub is closed , the serum IL-6 level will decrease by natural protein degradation.

Decrease in serum IL-6 during tocilizumab treatment may therefore indicate disease remission and may allow us to safely discontinue tocilizumab treatment without the risk of an acute flare.