18 |!,;IoZ
Jurkat cells cultured in calcium-free RPMI-1640 medium (Gibco BRL; number 'de&9\
22300-107) containing calcium-free 10% FBS were triggered by anti-Fas IgM. The :tdN#m6&
treated cells were harvested at the indicated time points and incubated with Fluo-3-AM at nD{o8;
a final concentration of 1 micromolar for 30 min at 37°C (Scoltock et al., 2000). The Iw~R@,
labeled cells (50,000 cells per treatment) were then analyzed by exciting the cells at 488 +<a-;e{
nm and examining the fluorescence emission of Fluo 3 at 530 nm with a FACS Scan, =+DfIO
(Becton Dickinson). A one micromolar concentration of LPA was used as a positive TD!--l*gL
control for Ca2+ induction. The data thus obtained was analyzed with the software Win ~}pc&jz>q
MDI 2.8 and represented as contour plots.The effect of chelating intracellular calcium on 8BE] A_X
translocation of annexin I was studied by culturing Jurkat cells in the presence of 10 S6Y2(qdP
micromolar BAPTA-AM, with or without the addition of anti-Fas IgM. Cells were J}BN}|Y@2
harvested and fractionated as detailed above, and the S-100 fractions were assessed by <hvs{}TS
immunoblotting for presence or absence of annexin I. 1-0tG+
Mouse bone marrow transduction and transplantation. r2yJ{j&s
Retrovirus-mediated transduction of mouse bone marrow cells was done by published Bs)'Gk`1
methods49. Prestimulated low-density bone marrow cells were infected with high-titer
Xdh2
retrovirus supernatant on fibronectin-coated plates. Retrovirus supernatant was generated hz:h>Hwy
in the phoenix-gp cells with a mouse stem cell virus–based retroviral vector coexpressing 0v+-yEkw
EGFP and HA–RhoH as described50. EGFP+ sorted cells were transplanted by }@x!r=O)I
intravenous injection into the sublethally irradiated (300 rads with a 137Cs irradiator) d^MRu#]
Rag2-/- recipient mice. At 9 weeks after transplantation, thymus, peripheral blood, bone ckGmwYP9
marrow, spleen and lymph nodes from each recipient mouse were collected for analysis
cX7 O*5C
of EGFP+ chimerism and hematopoietic lineage by flow cytometry. Expression of o3]Lrzh
HA–RhoH and HA–RhoHF73F83 in EGFP+ sorted thymocytes of recipient mice was ja^_Lh9
confirmed by immunoblot analysis. v{d$DZUs
Determination of renal morphology &hEn3u
Kidney slices were postfixed in buffered 2% OsO4, dehydrated, and embedded in an Z<^;Ybw{`Z
Araldite-EM bed 812 mixture. Large sections were cut perpendicular to the renal capsule, HS[($
containing cortex, and medulla. Thin (1 m) sections were analyzed in a blinded manner /sfJ:KP0
for morphologic alterations, as previously detailed .7]P-]uOZ
Patient population H2H`7 +I,
Patients included in the study met the following criteria: (1) biopsy-proven IMN; (2) ,qx^D
creatinine clearance 30 ml per min per 1.73 m2; and (3) persistent proteinuria >5 g per o^XDG^35`
24 h despite treatment with an HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Q$uv
\h;
reductase inhibitor, an ACEi, and/or ARB at maximal tolerated dose for at least 4 months. 84vd~Cf9
The Mayo Institutional Review Board and the Research Ethical Board, University Health @-}*cQ4u?
Network, University of Toronto approved the study protocol. All patients gave written fuzB;Ea
informed consent. Patients who had been on treatment with prednisone, cyclosporine, or [Ur\^wS
19 OvAhp&k
mycophenolic mofetil within the last 4 months or alkylating agents within the last 6 W:,Wex^9n
months were not included in the study. Patients with active infection, diabetes, or a gVrQAcJj
secondary cause of MN (for example, hepatitis B, systemic lupus erythematosus (SLE), 2]1u0-M5L
medications, malignancies) were also excluded. 4;fuS_(X
Treatment (J[Xryub
At enrollment, a low-sodium (<4 g day-1) and low-protein (0.8 g per kg per day of T]
\c2U
high-quality protein) diet was recommended and patients were encouraged to maintain yL*]_
the same diet throughout the duration of the study. All patients received a similar @(Y!$><Is
conservative treatment regimen that included loop diuretics to control edema, an MC* Hl`C
HMG-CoA reductase inhibitor, and an ACEi combined with an ARB if tolerated. 5?lc%,-&
-Blockers and non-dihydropyridine calcium channel blockers, in that order, were added $#q`
Y+;L2
when required to control systolic blood pressures to <135 mm Hg in >75% of the 0V4B Q:v
readings. Patients who after a minimum of 4 months of conservative therapy and e"ehH#i
maximized Ang II blockade had proteinuria >5 g per 24 h received two i.v. infusions of {uj_4F
t
rituximab at a dose of 1000 mg on days 1 and 15. To minimize infusion reactions, B
1V{
3
patients were premedicated with acetaminophen (1000 mg) and diphenhydramine ")T\_ME
hydrochloride (50 mg) orally. In addition, methylprednisolone (100 mg, i.v.) was given |5bLV^mv]i
prior to the first rituximab infusion. B-cell depletion was defined as CD19+ count uMJ\
<5 cells per l at any time and B-cell recovery was defined as CD19+ cell count $@>0;i::
>15 cells per l. Patients treated with rituximab, who at month 6 had proteinuria >3 g per Snx!^4+MF
24 h and in whom CD19+ B-cell counts had increased to >15 cells per l, received a $VuXr=f}
second course of rituximab treatment following the same protocol described above. c2y,zq|H
Follow-up "f,{d}u
In all patients, clinical and laboratory parameters including complete blood counts, m1l6
QcT1
electrolytes, serum albumin, B-cell flow cytometry for CD19+ B cells, serum CIjc5^Y2
immunoglobulin (IgG, IgM, IgA) levels, and a lipid panel were evaluated at study entry `7CK;NeT
and at months 1, 3, 6, 9, and 12. Creatinine clearance and protein and creatinine excretion p49]{2GXb
in the urine were assessed by performing two consecutive 24-h urine collections at each ~SnUnNDm `
time point. Data were considered accurate when urinary creatinine excretion was U ? +_\
consistent with a complete 24 h collection. The mean of the two measurements was s/E|Z1pg3
considered for the analysis. The presence of HACAs was evaluated at baseline and at yD7BZI
xW
months 3, 6, 9, and 12. ]:P7}Kpb
Method / Approach / Study/ Technique Bq q=
2lj
A discussion is presented of a problem-solving system \D7b
Tn
To improve the efficiency of the method, the following approach may be applied. gc9R;B1
In order to an investigation was made to find the causes of the [9 W@<p
Although large collections of rules and equations have been complied, none are generally i[v4[C=WB!
accepted xN 1P#
20 cHs3:F~~
This approach will be explained and discussed thoroughly in the body of the report. .Pb-{!$Ni
This can be accomplished by Lo%n{*if
This algorithm to compute the total cost can be described step by step as follows: J ^'El^F
The above preliminary analysis has provided important information ~r1pO#r-
Various methods have been proposed for selecting an optimum...
`o[l%I\Q
These concepts have been applied to b 7UJ
On the basis of the concept mentioned above, >STtX6h
This can be achieved by 3k
Ci5C
In addition, tissues were stained for infiltrating lymphocytes (CD20 and CD3), and the 5E]t4"
amount of interstitial fibrosis was quantified by histomorphometry. Formalin-fixed, xa>|
k>I
paraffin-embedded sections were cut onto coated glass slides. Following heat-induced
is'V%q
antigen retrieval, sections were incubated at 20°C overnight with either anti-CD20 "-J5!y*,Y
primary antibody or anti-CD3 primary antibody, both at 1:1000 dilution (Dako, Canada ;G[V:.o-
Inc, Mississauga, Ontario, Canada). After rinsing all sections, pretreatment with 3% 6Sr]<I +:
hydrogen peroxide was performed to prevent endogenous peroxidase activation. Sections |=?#Xbxz
were incubated with a secondary rabbit anti-mouse antibody linked with avidin–biotin iUx\3d,
complex. Sections were counterstained with hematoxylin and examined by light ,YYEn^:>
microscopy. RK3 yq$
The HACA assay is a proprietary bridging enzyme-linked immunosorbent assay 79\wjR!T
performed at Genentech Inc. that measures the antibody response to rituximab in human #[93$)Gd!
serum samples. z _!ut
In all patients, clinical and laboratory parameters including complete blood counts, 6TtB3;5
electrolytes, serum albumin, B-cell flow cytometry for CD19+ B cells, serum 5/meH[R\M
immunoglobulin (IgG, IgM, IgA) levels, and a lipid panel were evaluated at study entry i"8mrWb
and at months 1, 3, 6, 9, and 12. Ey6R/M)?:y
This fact suggests that a new concept 9d(\/
7
This was accomplished by taking ...
bGRt
The preparatory stage is very time consuming process. Dl,QCZeM
Test are performed for validity, completeness, and compatibility %uW=kr
There is little hope of achieving successful ... ^ Ltho`
There has been an increasing awareness of the potential of using most ..so far made have |)-kUu
not taken this approach, with the exception of dC11kqqj
Only a few studies can be found. N8<J'7%
It is a very tedious process to go through c_lHj#A(l
It is only when .. has been completed that .. may be effected @MW@mP)#
The entire interpretation process is conducted in one's head. g=*jKSZ
These approaches are sometimes very tedious. t
ne_]+
Several techniques can be used D6 B-#u!M
A polynomial parametric model can be written as [the following]/[follows]: nJDGNm,
A xx model is constructed/formulated using xx. G\.~/<Mg+
A xx model represents an xx by its xx. 1{}p_"s>
A process decision model captures the logic essential to SI (
f&T(
From the equation above, xx is equal to the summation of xx times the ... .@1+}0
21 h`[$
Bp
The validity of a xx model can be checked using Euler's formula. tUn>=>cWP
Given a model, one can mathematically determine whether ... or ... mScv7S~/s
Equations for xx need to be derived and implemented in the system. .)Tj}Im2p
A number of heuristic rules have been developed for v.0qE}'
|
Optimum .. techniques can be made more reliable by ... so that WI8}_){ d
An algorithm based on the characteristic ... is used to determine S
zULy
>e
Euler's formula states the following: oXPA<ef o
The completed model should agree with the formula. UwN Vvo
For manufacturing purposes, a detailed and precise model of the object is necessary 6
FS%9.Ws
Engineering design models are very well defined; therefore, Hv,|XE@Y
To keep the domain narrow enough to be implementable, yet wide enough to be useful. KK|w30\f
Point of View 2TK \pfD
from an implementation standpoint, &@=Jm
/5
From the point of view of this application, U(&c@
u%
From this point of view, Zadeh suggested an inference rule named xxx (CRI for short). ?K1B^M=8
Information is the meaningful interpretation and correlation of some aggregation of data r(,U{bU<
in order to allow one to make decisions. n#_B4UqW%
From a practical point of view, the computational aspects of an FLC require a MK<
y$B{}
simplification of the fuzzy control algorithm. o3WOp80hz
The use of a hammer to insert screws, although partly effective, tends to distort, destroy, woI5a ee|
and generally defeat the purpose of using a screw [Kusiak AI Implications for CIM }\_.Mg^y
p.129] [8V;Q
Statistical analysis bG;fwgAr
Data were analyzed by one-way analysis of variance comparing the three conditions 6 2xOh\(
(sham operation, ischemic AKI, and bilateral nephrectomy) at each time point. If # :+
Nr
significant F-statistic from analysis of variance existed, this test was followed by Dunnett d0J/"<
post hoc multiple comparison procedure with sham operation as the control group. For all (leX` SN0u
other comparisons, Student's t-test was used. A P-value of <0.05 was considered as "8za'@D"f
statistically significant. `kKssU<
Values are expressed as means s.e.m. and significance was evaluated by Mann–Whitney )\wkVAm
U test using GraphPad Prism, version 4.0 software (GraphPad Software Inc., San Diego, kBUkE-~
CA, USA). ;`AB-
All values are expressed as means s.d. Statistical significance (defined as P<0.05) was 7H
H
evaluated using analysis of variance and Bonferroni t-tests, and the two-tailed Pearson's %0\@\fC41
test, where appropriate. dCx63rF`G
Data are expressed as mean s.d., median and interquartile range, or frequencies, as >`QBN1 Y
appropriate. Variables who deviated from the normal distribution (positively skewed) =4TQ*;V:
were log-transformed (log10) before the correlation study. EKc<|e,F
Data are represented as means s.e.m. Student's t-test and multiple comparisons with t-test If'q8G3]-
post hoc analysis of variance were used as indicated below, for the comparison of VH7t^fb
22 C T~6T&'
morphological, immunohistological and functional parameters. Statistical significance /R&`]9].s
was set at P<0.05. j26i+Z
The primary efficacy parameter was defined as change in urinary protein excretion from 74^v('-2
baseline (week 0) to 12 months after treatment. The 12-month changes were tested FDoPW~+[
against zero using the paired t-test. Secondary end points included 6-month changes in 0kJ8H!~u
protein; the number with PR or CR at 6 or 12 months; and changes in glomerular 4Kqo>|C
filtration rate (GFR), serum albumin, and lipid profiles. Study sample size was based on 2EgvS!"
the desire to have 80% power to detect a drop in urinary protein of at least 2.0 g day-1. }L0
[Jo:
Assuming a two-sided hypothesis test performed at a significance level of 0.05 and an s.d. 8W3zrnc
of urinary protein change of 2.5 g, it was determined that 15 patients were required.2 9J:|"@)N
Definition of remission status is according to the criteria established by Cattran et al.30 xMbgBx4+
CR was defined as proteinuria <0.3 g per 24 h, PR as proteinuria 3 g per 24 h, and a 3ynkf77cn
>50% reduction in peak proteinuria and non-response as <50% reduction in peak CU=sQfE
proteinuria. Any patient reaching a CR or PR was considered a treatment success Z+B*V)a=
The statistical significance of differences for the mean values of cytokine concentration "#)|WVa=BM
and T cell proliferation was determined with Student's t-test. Differences with a P value _2KIe(,;
of less than 0.05 were considered significant. 8T+9
fh]I
Statistical significance was determined by Student's t-test. Data with a P value of less Nu qmp7C
than 0.05 were considered significant. d==0 @`
In vitro and in vivo experiments were analyzed by the two-tailed Student's t-test, with P R*GBxJaw
values less than 0.05 considered statistically significant. $
:I{
The significance of differences among groups was determined by Student's t-test and stG
+4w
one-way analysis of variance (SigmaStat software; Jandel). y)zZ:lyIq
Comparisons iM!Ya!
As well, the pros and cons of these representations from a process planning point of view yjT>bu]
will be discussed. {Q>OZm\+
The method of using xx to implement xx described by Zadeh (1973) appeared more a!R*O3
suitable a&{Y~Og?%
As discussed [in the previous section]/[preciously], J4+WF#xI2
Relation !h1:AW_iz
We can not invert F' directly because it defines a many-to-one mapping. a~Dk@>+P>
The relationships appear very complicate 1 G]D:9-?
Lifting tasks involve complex and imprecise relationship between the task variables and bci]"uzB
the human operator's characteristics. af<h2r
These methods are based on the relationship between ... and ... ?OW!D?
The fundamental concept of a fuzzy rating language is that we can establish a relationship @Ommd{0M
among terms such as high, medium, and low, and then modify these relationships. TG;[,oa
This article will thus mention the latter as well as the former. m 3UK`~ji
The former two bear a close relation to a fuzzy Cartesian product. uZ8-?
Importance u7mPp3ZYK
) nA0%M1a
23 mrr]{K
The emphasis is on an implementation of a general approach to rule based decision 2d*bF.
making. NWh1u`
Consideration / Attention M(L6PyEa!Y
Careful evaluation is necessary to ensure QM8Ic,QFvo
Such a formulation does not change further considerations. ,c"J[$i
$
Considerable attention has been paid to nrY)i_\
Attention should be paid to an important finding of this investigation. G_?U?:!AC
Caution should be exercised in this process to avoid ... YyYZD{^
Primary consideration is given to ... components, though others can be accommodated `Pc6
G*p
After ... has been defined by ..., a carefully analysis is carried out/performed to determine Btxtu"]nJo
A number of factors such as ...need to be taken into consideration before making the $F^VtCx2&
appropriate decision. M~\dvJ$cH
It should be noted that O|sk"YXF
It is important to point out that ... 7SS#V
These considerations have heightened interest in the possibility of providing ... =s!0EwDH3
We should stress the fundamental importance of the xx EF!J#N2
Results. fD@d.8nXd
Advantages / Disadvantage nHm29{G0
One of the major advantages of this new measure of xx is that it can be applied to the _%R^8FjH*
experimental study of W+;=8S
One advantage of using a .. is the ease of preparing it. &(,\~
It has a very fast decision making process Jy/<
{7j
All the algorithms involve mostly logical operations. AuK$KGCI=
It can be easily and without additional cost implemented in a microprocessor;based lS9S7`
environment. )qb'tZz/g_
It can reduce the waste of designing from scratch. S>I` y]qlR
The advantages of using a xx to represent xx are the following: EA(4xj&:U
However, xx is not without its shortcomings. 27fLW&b2
In most cases, the xxx shows an improvement over the existing xxx.
4ams~
Compared to the existing xx, the impacts of the xx are generally reduced by 5% to 9%. /V 09Na,N
The "best case" results shows a savings of 6% to 9%. ymxA<bICS8
Most of the existing works based on xx approach can only recognize a xx . 1s(T#jh
Most of the above methods are computational expansive and limited to xx. eMnK@J
Some other advantages of xx are the following: z |llf7:
The problem is the limitation of this method to a limited domain of parts. h_?`ESI~
It proved limited in application because it demanded precision in system modeling that Q&.uL}R
was impossible in practice. d^A]]Xg
There are advantages to be gained in the structuring of costs and benefits, the use of xx, z*h:Nt%.
The disadvantages of this method are also disadvantages of conventional xx approaches. iH4LZ
This combines the best features of both techniques rs?Dn6:;B
24 OJpfiZ@Q_
Hopefully, this tool can be as the reference framework of for developing a xx platform, WF`%7A39Af
and helping the administration, marketing, and knowledge management activities in zQulPU
virtual communities. " Bx@(
Results OU UV8K
An improvement on the result shown above can be made by based on the data provided H9)n<r
Recent work has identified ,:PMS8pS
Time-dependent changes of h,R Isq;`
Cyclosporine-induced cell death is triggered by a non-classical phosphoinositide 3-kinase 4+q,[m-$(
and does not require ERK activation. N_bgW QY
Much of the current work on 73rme,
Discussion of these theories is beyond the scope of this review :ZY%-]u7
Based on the information contained in this b_RO%L:"yL
The result can be categorized into nine classes :
B&~q$
The results are illustrated by an example :|s;2Y
The experimental results for each xx time are reported in Table 2. LH(P<k&
From the results obtained so far, it seem that Ck
)W=
Because of the inaccuracy of the ..., a conclusion cannot be drawn as J[:#(c&c!1
Although much effort has been made to., this reality is far from completion. m@XX2l9:9
The results indicate that the total benefits are higher than the total costs. L@GICW~
Their results may then serve as guidelines for lower level models, less fuzzy and more n#x_da-m]
detailed. Pv5S k8
Conclusion `15}jTi
From the discussion, one may conclude that ... #ae?#?/"
The first indication that ]|g2V
a~-
In summary, we have shown that UCcr>
These results suggested that ;)FvTm'"\.
Our findings have shown that O80Z7
Our observations have provided >
Hv9Xz
This study reveals following five main findings: P?V+<c{
To our knowledge, this is the first immunohistochemical report of both PIM and HIFs in m+'1c}n^7
the diabetic kidney. a?+C]u?_D
As mentioned above, \;Q(o$5<
Moreover, we demonstrate that, 8J'5%$3u
A number of studies have elaborated a body of knowledge about (E0WZ$f}
There are findings to indicate that .\oW@2,RA9
On a descriptive level, there is agreement that for YaS!YrpI
One issue that became particularly evident from our study is R?)Yh.vi=t
Our data are in agreement with the findings and models presented by previous (9]1
p;
publications, in particular those of Jones et al ThX3@o
According to our observations, .)tQ&2
…was not evident from our data Ewz cB\m
25 ^Ak?2,xB#+
It could therefore be concluded that uB"B{:Kz
our data illustrate that 9<rs3 84
All these different aspects, as listed above, lead to T4:H:
In fact, it has already been speculated that HR?T
It should be furthermore mentioned in this context that AAfU]4u0S
To identify and verify the essential factors triggering developmental renin expression, it ^!^M Gzu
is of interest now to study the development of intrarenal renin expression in mice with -_9*BvS]R
defined gene mutations, using the results of this study as a reference system. 2gK]w$H7!
In conclusion, using several approaches, we demonstrated that u^SInanw
But we have not provided formal proof yet that Sm {Sq
In summary, our results suggest that 02EX_tt),
In conclusion, we identify ]/h$6mrL
A better understanding of such regulatory systems may yield novel therapeutic v @M6D}
approaches to glomerular diseases. "\Dqtr w
Preliminary results of short-term studies (2 weeks) indicate that g
\S6>LG!
However, we believe that O6$,J12l
However, despite our extensive measurements of these parameters, we found no , SUx!o
relationship between response and initial proteinuria, time to B-cell recovery, the i;~.kgtq4
development of antibodies to rituximab, B-cell count in the kidney tissue, nor the degree W"s/8;
of tubular interstitial damage present. A clear conclusion for efficacy, however, cannot be ?i0u)<H
obtained from an uncontrolled study, and definitive claims of efficacy should be reserved XC<'m{^(m
for rigorous, prospective, controlled, and randomized trials with the use of rituximab and vO?sHh
that will also look for factors that may determine its efficacy in IMN. N:64Gko"K
It has become increasingly clear that "PTEt{qn
Form the above discussion, the conclusion can be reached that z{BgAI,
The conclusions drawn are also valid |#t^D.j
In conclusion to this, it becomes obvious that the problem of xx lies not only in... 3bGU;2~}
We have attempted to introduce some concepts associated with a theory of `yl|NL
Considerable more work, hopefully, will be done in this area 1k
"t[^
Employing the compositional rule of inference, the assessment of the xx compatibility in =_E$* }
achieving prescribed xx projectiles in any level of the hierarchy is made possible.
|4BD
This paper has presented a theoretical and experimental study of the xx process and xx %! Sjbh
concept. "}0QxogYE
The experimental research results will hopefully serve as useful feedback information for G?~Yw'R^8
improvements for xx work. pdN8hJ
The scope of this contribution was to introduce a xx method. V`/c#y||
This has a tremendous impact on our understanding of n|.eL8lX.<
Significant progress has been made in advancing RNAi therapeutics in a remarkably e
GAto
short period of time qMVuBv
To date, little is known about… `\z )EoI
Irrespective of the mechanisms and the molecules –which are still largely unknown – V@z/%=PJ
involved in MSC functions, current data suggest that Mf5*Wjz.Mc
To better understand 2sqH
>fen
26 dJQwb
Future Research (常用于conclustion 的结尾) Iza#v0
Thus, first extension of the approach could be, m(xyEU
Further studies are needed to determine the importance of }#Ji"e
Some improvements to the scheduling aspect of the model may be brought through UY *Z`$
additional levels in the hierarchy for more detailed representation of the scheduling ~
r})&`5
activity. `]6W*^'PD
It also unveiled new aspects of the role played by thyroid hormone in response to injury 6~!7?F
K
and tissue repair. \,nhGh
In the near future, the ongoing clinical trials with siRNAs for macular degeneration and DM)Re~*
RSV may reveal the exciting potential of RNAi therapeutics as the next major class of Q'e[(^8
drug molecules. H%>cpwa[7
In the next few years it should become clear whether (A_H[xP
It should be an exciting time for researchers seeking to harness this powerful endogenous M@. 2b.
pathway to treat human disease. F&+_z&n