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Infliximab as a bridge to remission maintained by antimetabolite therapy in Crohn's disease

Digestive and Liver Disease 46(2014)695–700

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Digestive and Liver

Disease

j o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /d l

Alimentary

Tract

In?iximab as a bridge to remission maintained by antimetabolite therapy in Crohn’s disease:A retrospective study

Armelle Chauvin a ,Aurelie Le Thuaut b ,c ,d ,Mehdi Belhassan a ,Yann Le Baleur a ,

Farida Mesli a ,Sylvie Bastuji-Garin b ,c ,d ,Jean Charles Delchier a ,Aurelien Amiot a ,b ,?

Assistance Publique-H?pitaux de Paris (APHP),Paris Est Creteil University (UPEC),Henri Mondor Hospital,Department of Gastroenterology,Creteil,France b

Paris Est Creteil University (UPEC),Laboratory of Clinical Investigation (LIC,EA 4393),Creteil,France c

Assistance Publique-H?pitaux de Paris (APHP),Henri Mondor Hospital,Department of Public Health,Creteil,France d

Assistance Publique-H?pitaux de Paris (APHP),Henri Mondor Hospital,Clinical Research Unit (URC Mondor),Creteil,France

a r t i c l e

i n f o

Article history:

Received 23January 2014Accepted 27April 2014

Available online 2June 2014

Keywords:

Crohn’s disease IBD

In?ammatory bowel disease In?iximab withdrawal

a b s t r a c t

Background:In?iximab withdrawal in patients with Crohn’s disease on concomitant antimetabolite ther-apy is considered to be superior if obtained after a maintenance therapy period compared to induction alone.

Methods:We retrospectively analyzed the outcome of Crohn’s disease patients treated with in?iximab and an antimetabolite after in?iximab was withdrawn using induction alone or induction plus at least 1-year of maintenance therapy.The time to relapse was analyzed using univariate and multivariate analyses.The model was adjusted according to the period of in?iximab withdrawal.

Results:A total of 92patients were included,54in the induction alone group.The patient characteristics were identical in the two groups except for the period of in?iximab withdrawal.After a median follow-up period of 47.1(interquartile range =4.4–110.2)months,66patients (72%)experienced a relapse.After a year-adjustment,no signi?cant difference was observed between the two groups.Based on year-adjusted multivariate analysis,the risk factors for relapse were active smoking,previous antimetabolite failure,and perianal disease.After relapse,53patients (80%)were retreated with in?iximab.After in?iximab retreatment,clinical remission was observed in 47patients (89%)at weeks 8–10.

Conclusion:In Crohn’s disease patients,the probability of relapse on antimetabolite therapy after in?ix-imab withdrawal was not superior after a 1-year scheduled maintenance therapy as compared with an induction alone.

1.Introduction

The advent of anti-tumour necrosis factor (TNF)agents has established new goals for the management of Crohn’s disease (CD).In addition to controlling disease activity,anti-TNF therapy reduces the need for hospitalization and surgery while also improving patient quality of life [1–5].However,the economic burden of long-term anti-TNF therapy and the desire of patients to discontinue medication support a strategy of drug withdrawal.If and when a patient should cease in?iximab treatment for CD remains a debated issue.A study from the Groupe d’Etude Thérapeutique des Affec-tions In?ammatoires du tube Digestif (GETAID)has evaluated the outcome of patients treated with azathioprine and induction ther-?Corresponding author at:51,Avenue du Marechal de Lattre de Tassigny,Creteil F-94010,France.Tel.:+33149814358/149812362;fax:+33149812352.

E-mail address:aurelien.amiot@hmn.aphp.fr (A.Amiot).

apy with in?iximab [6].In this study,113CD steroid-dependent patients were randomized to receive either in?iximab at week 0,2and 6,or placebo.The rate of steroid-free remission was signi?-cantly higher in the in?iximab group than in the placebo group at weeks 12,24and 52(75%,57%and 38%,respectively)but decreased over time.Patients who had reached steroid-free remission at the end of the study were further evaluated for up to 4years,and the data demonstrated that in?iximab was no longer superior to placebo [7].

Recently,Louis et al.prospectively evaluated the outcome of CD patients using combined therapy after in?iximab was discontin-ued in patients with prolonged remission longer than 6months [8].After one year,the rate of relapse was 43.9%(±5.0).An anal-ysis of the clinical and biological markers de?ned a group with a low risk of relapse.The authors concluded that Crohn’s disease patients in stable remission treated with combined therapy con-sisting of in?iximab and an antimetabolite could safely withdraw from in?iximab.Re-treatment with in?iximab was effective and

https://www.wendangku.net/doc/d68397740.html,/10.1016/j.dld.2014.04.012

696 A.Chauvin et al./Digestive and Liver Disease46(2014)695–700

well tolerated in patients who experienced a relapse.In the absence of any controlled study,further data are warranted.

The aim of this study was to compare the outcome of CD patients in stable remission treated with combined therapy consisting of in?iximab and then an antimetabolite after in?iximab was discon-tinued,after induction therapy alone or induction plus at least one year of scheduled maintenance therapy.

2.Methods

2.1.Patients

We retrospectively reviewed consecutive case records of all adult CD patients referred to Henri Mondor university hospital in Paris,France from January2000to June2012.Patients were recruited from our personal database and/or a standardized hos-pital inpatient dataset.The patients eligible for this study were at least17years of age and had received combined in?iximab and antimetabolite treatment for active CD.All patients had discontin-ued in?iximab treatment but maintained antimetabolite therapy. The decision of withdrawing in?iximab was made according to a consensus between the physician in charge and the patient without any restriction from the public health care system.Eight patients from this series have already been included in a prospective mul-ticenter study from the GETAID[8].The exclusion criteria for this study included the following:a history of severe acute or delayed infusion reaction to in?iximab,initial indication for in?iximab being predominantly manifested extra-intestinally without signif-icant CD activity,persistence of active luminal and/or?stulizing disease,an ostomy,pregnancy or lactation.The study inclusion dates were from January2009to June2012.The protocol was approved by the appropriate ethics committee.

2.2.Treatments

2.2.1.In?iximab

All patients were na?ve to in?iximab at entry.The patients received either an infusion of in?iximab administered at a dose of5mg/kg at weeks0,2,and6(induction group)or an infusion of in?iximab administered at a dose of5mg/kg at weeks0,2and 6,followed by scheduled infusions at a dose of5mg/kg every8 weeks for at least one year(maintenance group).All patients were treated with intravenous hydrocortisone premedication(200mg) before each in?iximab infusion.

2.2.2.Antimetabolite therapy

All patients were treated with azathioprine≥2mg/kg/d, mercaptopurine≥1.5mg/kg/d or methotrexate25mg weekly sub-cutaneously or intramuscularly.The patients had stable doses of antimetabolite therapy for at least3months.Regarding antimetabolite status at baseline,two types of patients were eli-gible:those who had still active disease despite receiving the underlying antimetabolite for more than6months for thiopurine and3months for methotrextate(previous antimetabolite failure group)and those who did not receive the underlying antimetabo-lite in the past history or who have withdrawn it despite clinically proven ef?cacy.

2.2.

3.Treatment cessation

All patients had to be in stable remission as assessed by a Harvey-Bradshaw score<4at the time of in?iximab withdrawal. The patients were followed-up with from the time of the last in?iximab infusion.The clinical and demographic data collected included patient age at diagnosis,gender,smoking habits,CD phenotype according to Montreal classi?cation,and a history of medical and surgical treatment for CD[9].The biological data col-lected included CRP(mg/L),haemoglobin(g/dL),leucocyte counts (/mm3)and platelets(/mm3).In a subgroup of the patients,an ileo-colonoscopy was performed in the6months preceding in?iximab withdrawal.Mucosal healing was de?ned as the absence of ulcers

[10].The Harvey-Bradshaw index was calculated in cases of relapse.

A relapse was de?ned by a Harvey Bradshaw index above4points or the need to introduce any speci?c treatment for CD[11].

2.3.Follow-up after relapse and re-treatment

In cases of relapse,the patients were re-treated by their pri-mary physician.Re-treatment with in?iximab was conducted with either re-induction followed by scheduled infusion every8weeks or scheduled infusion every8weeks without an induction phase. All patients experiencing a relapse were assessed for response and tolerance to treatment8–10weeks after the?rst in?iximab re-treatment and until the end of follow-up.In addition,for patients who experienced a relapse and were not re-treated,information regarding treatment and surgery was also collected.

2.4.End points

The primary end point was time to relapse after in?iximab with-drawal and the identi?cation of risk factors associated with the relapse.A relapse was de?ned by a Harvey Bradshaw index above 4points or the need to introduce any speci?c treatment of CD[11]. The secondary end points were safety and ef?cacy of re-treatment with in?iximab in patients who experienced a relapse.

2.5.Statistical analysis

The patient characteristics are described as number(%)for qual-itative data and as median(interquartile range,IQR)or mean(±1 standard deviation,SD)for quantitative data according to their dis-tribution.We compared the baseline characteristics of the patients in both groups(induction and maintenance groups)using the Pear-son chi-squared test or Fisher’s exact test for qualitative variables and the Wilcoxon non-parametric test for quantitative variables.

The time to relapse after in?iximab withdrawal was assessed using the Kaplan–Meier method,and the groups were compared using a log-rank analysis.A hazard ratio(HR)with95%con?dence interval(CI)was estimated using a Cox proportional hazard model adjusted for the year of in?iximab withdrawal.Other factors poten-tially associated with relapse were also analyzed.The proportional hazards assumption was graphically assessed for all variables.Vari-ables showing p<0.15in a univariate analysis were considered to be potential adjustment variables for multivariate analysis.Multi-ple2×2analyses were performed to assess?rst-order interactions and confounding variables.This approach was also used to select the adjustment variables included in the?nal analysis.

All comparisons were two-tailed,and p-values less than0.05 were considered signi?cant.Analyses were performed using STATA statistical software SE11(Stata Inc.,College Station,TX,USA).

3.Results

3.1.Patient characteristics

Ninety-two patients(57females;median age at inclusion32.6 [IQR=23.9–44.4]years)ful?lled the inclusion criteria.Table1 shows the patient demographic and CD characteristics.All patients were treated with stables doses of antimetabolite therapy for a median duration of11.0months(range,93.6–25.0).Fifty-four patients were included in the induction group,and38patients were in the maintenance group.The median follow-up period

A.Chauvin et al./Digestive and Liver Disease46(2014)695–700697 Table1

Baseline patients’characteristics.N=92patients,presented as number(%)or median(interquartile range).Pearson chi-square test or Fisher’s exact test and Wilcoxon non parametric test were used whenever appropriate.

Overall population(n=92)Maintenance group(n=38)Induction group(n=54)p

Female,n(%)57(62%)27(71%)30(56%)0.13 Age at diagnosis(years)23(19–33)22(19–29)24(19–34)0.41 Age at in?iximab start(years)32(24–43)30(24–42)33(23–44)0.65 Follow-up(years)47.1(4.4–110.2)38.4(4.4–66.9)55.0(10.2–110.2)<0.001

Active smoker38(41%)17(45%)21(39%)0.57 History of intestinal resection,n(%)13(14%)7(18%)6(11%)0.37 Perianal lesions,n(%)33(36%)11(29%)22(41%)0.25 Disease location

Ileal20(22%)8(21%)12(22%)

Colonic28(30%)13(34%)15(28%)

Ileocolonic44(48%)17(45%)27(50%)0.75

Disease phenotype

Non stricturing,non?stulising58(63%)25(66%)33(61%)

Stricturing and/or?stulising34(37%)13(34%)21(39%)0.65 Concomitant immunomodulator

Thiopurine87(95%)36(95%)51(94%)0.99 Methotrexate5(5%)2(5%)3(6%)0.99 History of antimetabolite failure37(40%)19(50%)18(33%)0.11 Laboratory tests

Haemoglobin level(g/L)13.3(12.2–14.1)13.4(12.2–14.4)13.0(12.1–13.9)0.28 Leukocytes count(109/L)5630(4200–7700)5900(4200–7700)5500(4300–8100)0.99 hsCRP level(mg/L)3(2–7)3(2–6)4(2–8.5)0.35 Mucosal healing18/30(60%)17/25(68%)1/5(20%)0.13 Date of in?iximab withdrawal

Before200654(59%)6(16%)48(89%)<0.001 After200638(41%)32(84%)6(11%)<0.001 hsCRP,high sensitivity C-reactive protein.

was47.1months(range,4.4–110.2)for the overall population, 55.0months(range,10.2–110.2)for the induction group and38.4 months(range,4.4–66.9)for the maintenance group.The2treat-ment groups were comparable for all clinical characteristics,except for the period of in?iximab withdrawal(Table1).In the induc-tion group,48patients(89%)withdrew in?iximab before2006,and the remaining6patients withdrew after2006.In the maintenance group,6patients(16%)withdrew in?iximab before2006,and the remaining32withdrew after2006.Mucosal healing was assessed in30patients overall(33%);25in the maintenance group(66%) and5in the induction group(9%).Twenty-three of30patients had complete mucosal healing de?ned as the absence of ulcers.

3.2.Clinical relapse

At the end of the follow-up period,66patients(72%)experi-enced a relapse,including40in the induction group(74%)and26 in the maintenance group(68%,p=0.55).The overall median time to relapse was26.7months(range,7.8–75.4).There was a trend towards a longer median time to relapse in the induction group that did not reach signi?cance(32.7months,range14.1–78.2vs.15.9 months,range6.0–46.0).The1-and2-year treatment free remis-sion rates were70%and52%in the overall population(Fig.1).The1-and2-year treatment free remission rates were78%and60%in the induction group,and56%and36%in the maintenance group(Fig.2). The difference between the induction and the maintenance groups was not signi?cant even after adjustment for the year of in?iximab withdrawal(HR=0.73IC95%[0.41–1.30],p=0.29).

3.3.Risk factors associated with clinical relapse

By univariate analysis,clinical relapse was associated with a his-tory of antimetabolite failure(p=0.001),gender(p=0.002),active smoking(p=0.04),familial history of IBD(p=0.07),haemoglobin level>13g/dl(p=0.12),prior use of in?iximab(p=0.14)and peri-anal disease(p=0.15)(Table2).A patient strati?cation based on gender was made due to signi?cant differences between male and female patients.Based on year-adjusted multivariate analysis, the risk factors for relapse were active smoking(HR=1.91IC95% [1.11–3.27],p=0.02),previous antimetabolite failure(HR=1.78IC 95%[1.07–2.97],p=0.03),and perianal disease(HR=1.72IC95% [1.02–2.89],p=0.04).There was a trend towards higher relapse rates in male patients in the maintenance group(HR=2.73IC95% [0.98–7.62],p=

0.06).

Fig.1.Kaplan–Meier relapse-free survival curves.

698

A.Chauvin et al./Digestive and Liver Disease 46(2014)695–700

Table 2

Predictors measured at inclusion associated with time to relapse.

Risk factors

Univariate analysis

Multivariate analysis

Year-adjustedHR (95%CI)

Log-rank p -Value

Year-adjustedHR (95%CI)

p -Value Induction group Male 1

––Female

3.42(1.70–6.86)

–

–Maintenance group Male 2.67(0.98–7.25) 2.73(0.98–7.62)0.06Female

2.84(1.28–6.28)

0.01

0.96(0.50–1.84)

0.91

Age at diagnosis ≤20years 1

>20years

0.91(0.56–1.51)

0.73

–

Age at in?iximab start ≤30years 1

>30years

0.89(0.55–1.46)

0.66

–

Disease duration <4years 1

≥4years

0.95(0.58–1.54)

0.82

–

Active smoking No 1

Yes

2.10(1.27–

3.48)

0.004

1.91(1.11–3.27)

0.02

History of intestinal resection No 1

Yes

1.03(0.61–1.75)

0.91

–

Perianal disease No 1

Yes

1.44(0.87–

2.39)

0.15

1.72(1.02–

2.89)

0.04

Disease location Ileal 1

Colonic 1.55(0.75–3.19)Ileocolonic

1.68(0.85–3.29)

0.31

–

3.4.Outcome of re-treatment in relapses

Fifty-three (80%)patients were re-treated with in?iximab.There were 40patients in the induction group (74%)and 26patients in the maintenance group (68%,p =0.55).Re-treatment with in?iximab was conducted with a re-induction in 43patients (81%)and with a single infusion in 10patients (19%).In?iximab was continued using scheduled maintenance therapy every 8weeks.

After in?iximab re-treatment,all patients were assessed at week 8–10.A steroid-free remission was observed in 47patients (89%)at week 8–10.No differences were found between the induction and the maintenance groups (72%vs .86%,p =0.32).After a median

delay

Fig.2.Kaplan–Meier relapse-free survival curves according to the modality of in?ix-imab withdrawal.

of 1.2years (range,0.3–2.4),38patients (72%)were still in steroid-free remission with in?iximab therapy.The in?iximab failure-free survival was higher in patients who were retreated more than 12months after in?iximab withdrawal (p =0.001)but did not differ between induction and maintenance groups (p =0.26).

There were 13relapse patients who were not re-treated with in?iximab.Their rescue therapy included adalimumab (n =5),sur-gical resection (n =3),and steroids followed by a switch to another antimetabolite (n =4)and cyclosporin (n =1).

3.5.Safety

Seven infusion-related reactions were identi?ed.All reactions were occurred during a re-induction phase using three in?iximab infusions.Six infusion-related reactions were noticed in the induc-tion group,and there was one reaction in the maintenance group (19%vs.5%,p =0.22).Four infusion-related reactions occurred dur-ing the re-induction phase,and 3reactions occurred during the ?rst 6months after in?iximab re-treatment.

4.Discussion

Our study reports the clinical outcomes in 92patients with CD in stable steroid-free remission on combined therapy after in?iximab was discontinued but antimetabolite treatment was maintained.To our knowledge,this is the largest collection of CD patients eval-uated at a single centre comparing in?iximab withdrawal after induction therapy alone and after at least 1-year scheduled main-tenance therapy.In our cohort,the 1-and 2-year treatment-free remission rates were 70%and 52%.There was no bene?t of the maintenance group compared to the induction group.

A.Chauvin et al./Digestive and Liver Disease46(2014)695–700699

It is not clear how in?iximab therapy should be managed in patients who have achieved clinical remission.Indeed,anti-TNF agents have revolutionized the management of CD[12].In addition to controlling disease activity,these agents offer the possibility to reverse the pathological process that leads to bowel destruction and can improve quality of life for CD patients[3,4,13].However, clear risks of adverse events have been reported,including oppor-tunistic infection,paradoxical reaction and neoplasia[14–17].The economic burden of the long-term use of anti-TNF agents is also a major issue.Furthermore,the longer a patient is in remission,the more they may want to discontinue a medication and the less likely they are to adhere to therapy maintenance[18].Therefore,the pos-sibility of a drug“holiday”should be considered in patients with a low risk of recurrence after drug discontinuation.

Beyond these considerations,it is mandatory to ensure that clinical remission will be maintained over the long term after in?ix-imab is discontinued.Lemann et al.have reported that the1-year relapse rate on thiopurine therapy after an in?iximab induction alone was62%.Recently,the same group showed that the1-year relapse rate was43%in patients who had stable remission after maintenance in?iximab therapy for at least12months.Schnitzler et al.reported the experience of the Leuven University hospital.In this study,110patients had withdrawn from in?iximab therapy after a median time of6.2months,and84%of patients were in remission while continuing on antimetabolite therapy.The remis-sions persisted for a median of47.3(20.8–66.4)months.In our study,72%of the patents experienced a clinical relapse after a median follow-up of5.5years.Clinical relapse occurred in most cases in the?rst2years after in?iximab withdrawal.Furthermore, there was no bene?t of1-year maintenance therapy compared to induction alone in terms of clinical remission after in?iximab with-drawal.

Establishing potential risk factors for relapse is crucial to deter-mine which patients should maintain in?iximab therapy.Lemann et al.reported that clinical relapse was associated with a high CDAI at baseline,a young age,small-bowel involvement and a short duration of steroids before entry[6].In the STORI trial,risk fac-tors of clinical relapse were male gender,the absence of surgical resection,leucocyte counts>6000/mm3,haemoglobin<14.5g/dL, C-reactive protein>5.0mg/L,and faecal calprotectin>300?g/g[8]. In our series,we found active smoking,previous antimetabolite failure and perianal disease were risk factors for clinical relapse.

The formation of anti-in?iximab antibodies has been previously correlated with loss of response and/or increased risk of infusion-related reactions[19].Recently,Ben Horin et al.demonstrated that titres decline to undetectable levels within12months after in?ix-imab is withdrawn in the majority of patients[20].Laharie et al. previously reported that postponed retreatment with in?iximab in CD primary responders should be administered at least12months after in?iximab withdrawal for better ef?cacy and tolerance[21]. In our series,retreatment with in?iximab was also associated with safety and ef?cacy in patients who have been retreated more than 12months after in?iximab withdrawal.

Another important issue is the modality of in?iximab re-induction after treatment cessation.It is still unclear whether in?iximab should be restarted resuming the previous scheduled treatment at the same dose and frequency as before withdrawal or if restarting with a three-dose induction regimen is superior.In the STORI trial,patients in relapse following in?iximab withdrawal were re-treated with in?iximab with a single infusion.Thirty days after re-treatment with in?iximab,93%of patients were in remis-sion.None of the patients experienced an infusion-related reaction, despite a“drug holiday”.Similar?ndings have been reported in a Danish single centre study[22].In our study,77patients were re-treated with in?iximab.There were47patients(80%)treated using a three-dose regimen and12patients(20%)treated with a single dose regimen.At week10,86%of patients were in clinical remission.Seven infusion-related reactions were noted, and all were associated with a three-dose regimen.Six of the7 patients were in the induction group.Our data suggest that re-induction using a single-dose regimen is preferred for in?iximab re-treatment.

There are several limitations to our study.First,there was not a systematic assessment of the mucosal healing before in?iximab therapy cessation(30of92patients).This is related to the ret-rospective nature of our study and the rarity of mucosal healing assessment in the induction group.Second,the median disease duration before in?iximab withdrawal was4.1years(1–12.6).It is conceivable that these data are not applicable for all the subpop-ulations of CD patients.In the STORI trial,the median duration of CD before in?iximab therapy was7.8years(range,4.5–11.9).In the Lemann study,the median was5years(range,4–10)in the thiop-urine failure group and3years(range,1–6)in the naive group. In?iximab therapy has dramatically evolved over time by avoid-ing episodic treatment and optimizing therapy based on mucosal healing and trough levels[12].In the present study,the12-year inclusion period and small sample size may have led to bias in the selection of the patients(Supplementary Table S1).However,it was necessary to ascertain a difference between the two strategies of in?iximab withdrawal.

In conclusion,for CD patients in stable remission using com-bined therapy consisting of in?iximab and an antimetabolite, in?iximab withdrawal is feasible with a52%risk of relapse after2years.There was no bene?t of a previous scheduled therapy compared to induction alone.We identi?ed new param-eters associated with clinical relapse such as previous failure of antimetabolite therapy,active smoking and perianal lesions.Those factors should be taken into account before considering in?iximab withdrawal.

Con?ict of interest

AA has received payment for lectures from Biocodex and MSD and travel accommodation from Abbvie,MSD and Biocodex.None of the remaining authors have any potential con?icts to disclose about the present study.

Appendix A.Supplementary data

Supplementary data associated with this article can be found,in the online version,at https://www.wendangku.net/doc/d68397740.html,/10.1016/j.dld.2014.04.012. References

[1]Sandborn WJ,Hanauer SB,Rutgeerts P,et al.Adalimumab for mainte-

nance treatment of Crohn’s disease:results of the CLASSIC II trial.Gut 2007;56:1232–9.

[2]Colombel JF,Sandborn WJ,Reinisch W,et al.In?iximab,azathioprine,or

combination therapy for Crohn’s disease.New England Journal of Medicine 2010;362:1383–95.

[3]Feagan BG,Panaccione R,Sandborn WJ,et al.Effects of adalimumab therapy on

incidence of hospitalization and surgery in Crohn’s disease:results from the CHARM study.Gastroenterology2008;135:1493–9.

[4]Lichtenstein GR,Yan S,Bala M,et al.In?iximab maintenance treatment reduces

hospitalizations,surgeries,and procedures in?stulizing Crohn’s disease.Gas-troenterology2005;128:862–9.

[5]Peyrin-Biroulet L,Deltenre P,de Suray N,et al.Ef?cacy and safety

of tumor necrosis factor antagonists in Crohn’s disease:meta-analysis of placebo-controlled trials.Clinical Gastroenterology and Hepatology 2008;6:644–53.

[6]Lemann M,Mary JY,Duclos B,et al.In?iximab plus azathioprine for

steroid-dependent Crohn’s disease patients:a randomized placebo-controlled trial.Gastroenterology2006;130:1054–61.

[7]Costes L,Colombel JF,Mary JY,et al.Long term follow-up of a cohort of

steroid-dependent Crohn’s disease patients included in a randomized trial eval-uating short term in?iximab combined with azathioprine.Gastroenterology 2008;134:A134.

700 A.Chauvin et al./Digestive and Liver Disease46(2014)695–700

[8]Louis E,Mary JY,Vernier-Massouille G,et al.Maintenance of remission among

patients with Crohn’s disease on antimetabolite therapy after in?iximab ther-apy is stopped.Gastroenterology2012;142,63–70.e5;quiz e31.

[9]Satsangi J,Silverberg MS,Vermeire S,et al.The Montreal classi?cation of

in?ammatory bowel disease:controversies,consensus,and implications.Gut 2006;55:749–53.

[10]Neurath MF,Travis SP.Mucosal healing in in?ammatory bowel diseases:a

systematic review.Gut2012;61:1619–35.

[11]Harvey RF,Bradshaw JM.A simple index of Crohn’s-disease https://www.wendangku.net/doc/d68397740.html,ncet

1980;1:514.

[12]D’Haens G,Panaccione R,Higgins PD,et al.The London Position of the World

Congress of Gastroenterology on Biological Therapy for IBD with the Euro-pean Crohn’s Colitis Organization:when to start,when to stop,which drug to choose,and how to predict response?American Journal of Gastroenterology 2011;106:199–212.

[13]Pineton de Chambrun G,Peyrin-Biroulet C,Lemann M,et al.Clinical impli-

cations of mucosal healing for the management of IBD.Nature Reviews Gastroenterology and Hepatology2010;7:15–29.

[14]Beaugerie L.Immunosuppression-related lymphomas and cancers in IBD:how

can they be prevented.Digestive Diseases2012;30:415–9.

[15]Ford AC,Peyrin-Biroulet C.Opportunistic infections with anti-tumor necro-

sis factor-alpha therapy in in?ammatory bowel disease:meta-analysis of randomized control trials.American Journal of Gastroenterology2013, https://www.wendangku.net/doc/d68397740.html,/10.1038/ajg.138.[16]Cleynen I,Vermeire S.Paradoxical in?ammation induced by anti-TNF agents

in patients with IBD.Nature Reviews Gastroenterology and Hepatology 2012;9:496–503.

[17]Siegel C,Marden SM,Persing SM,et al.Risk of lymphoma associated with com-

bination anti-tumor necorsis factor and immunomodulator therapy for the treatment of Crohn’s disease:a meta-analysis.Clinical Gastroenterology and Hepatology2009;7:874–81.

[18]Lopez A,Billioud V,Peyrin-Biroulet C,et al.Adherence to anti-TNF therapy

in in?ammatory bowel diseases:a systematic review.In?ammatory Bowel Diseases2013;19:1528–33.

[19]Baert F,Noman M,Vermeire S,et al.In?uence of immunogenicity on the

long-term ef?cacy of in?iximab in Crohn’s disease.New England Journal of Medicine2003;348:601–8.

[20]Ben-Horin S,Mazor Y,Yanai H,et al.The decline of anti-drug antibody titres

after discontinuation of anti-TNFs:implications for predicting re-induction outcome in IBD.Alimentary Pharmacology and Therapeutics2012;35: 714–22.

[21]Laharie D,Chanteloup E,Chabrun E,et al.The tolerance and ef?cacy of a post-

poned retreatment with in?iximab in Crohn’s disease primary responders.

Alimentary Pharmacology and Therapeutics2009;29:1240–8.

[22]Steenholdt C,Molazahi A,Ainsworth MA,et al.Outcome after discontinuation

of in?iximab in patients with in?ammatory bowel disease in clinical remission: an observational Danish single center study.Scandinavian Journal of Gastroen-terology2012;47:518–27.

英特尔i3_i5_i7处理器型号及参数总览表+CPU型号大全

英特尔i3/i5/i7处理器型号及参数总览表请仔细看完本文，看完后你将会对笔记本芯片有一定了解，买笔记本才不会被JS坑骗。 ~~Kiong 前言：随着英特尔全新32nm移动处理器的推出，英特尔移动处理器大军的规模进一步膨胀。粗略地计算一下，现在市场上可以买到的Core i、酷睿2、奔腾双核、赛扬双核、凌动处理器几大家族的成员已经超过了80款，即使是经常关注笔记本技术的达人，也很难记住每一款处理器的技术规格。名词解释前端总线：是指CPU与北桥芯片之间的数据传输总线，人们常常以MHz表示的速度来描述总线频率。总线的种类很多，前端总线的英文名字是Fr Bus，通常用FSB表示。睿频：英特尔睿频加速技术。是英特尔酷睿i7/i5 处理器的独有特性。也是英特尔新宣布的一项技术。英特尔官方技术解释如下：当启动一个运行程序后，处理器会自动加速到合适的频率，而原来的运行速度会提升10%~20% 以保证程运行；应对复杂应用时，处理器可自动提高运行主频以提速，轻松进行对性能要求更高的多任务处理；当进行工作任务切换时，如果存和硬盘在进行主要的工作，处理器会立刻处于节电状态。这样既保证了能源的有效利用，又使程序速度大幅提升。三级缓存（L3）：目前只有酷睿I系列才有，之前的都是L2（二级缓存）。是为读取二级缓存后未命中的数据设计的—种缓存，在拥有三级缓存的CPU 有约5%的数据需要从内存中调用，这进一步提高了CPU的效率。制程：制程越小越好。越来越高的工艺制程可以提高芯片的集成度，增加晶体管的数量，扩展新的功能。同时随着晶体管尺寸的缩小，每颗的单位成本也有所降低。此外，更高的工艺制程可以帮助降低CPU的功耗，另外，降低CPU的成本以前扩大CPU产能也是新工艺制的积极影响。 TDP：TDP的英文全称是“Thermal Design Power”，中文直译是“散热设计功耗”。主要是提供给计算机系统厂商，散热片/风扇厂商，以及商等等进行系统设计时使用的。一般TDP主要应用于CPU，CPU TDP值对应系列CPU 的最终版本在满负荷(CPU 利用率为100%的理能会达到的最高散热热量，散热器必须保证在处理器TDP最大的时候，处理器的温度仍然在设计范围之内。注意：由于CPU的核心电压与核心电流时刻都处于变化之中，这样CPU的实际功耗（其值：功率P＝电流A×电压V）也会不断变化TDP值并不等同于CPU的实际功耗，更没有算术关系。

Intel(英特尔)、AMD(超微)所有CPU型号大全

Intel（英特尔）、AMD(超微)所有CPU型号大全英特尔的处理器有以下品牌： ?英特尔? 酷睿? 处理器 ?英特尔? 奔腾? 处理器 ?英特尔? 赛扬? 处理器 ?英特尔? 凌动? 处理器 ?英特尔? 至强? 和安腾? 处理器英特尔? 酷睿? i7-975 处理器至尊版世界上性能最强的台式机处理器。1 借助英特尔? 酷睿? i7 处理器 975 至尊版的智能化表现，释放台式机计算潜能，轻松应对复杂的多线程游戏和应用。英特尔? 酷睿? i7 处理器至尊版用世界上最快的处理器征服极致游戏世界：英特尔? 酷睿? i7 处理器至尊版。1 更快速的智能多核技术，满足您的各类需求，带来难以想象的突破性游戏体验。英特尔? 酷睿? i7 处理器智能多核技术速度更快，能够自动为最需要的应用提供处理能力。借助该技术，新的英特尔? 酷睿? i7 处理器将能为您带来惊人的突破性计算性能。这是全球最好的台式机处理家族。英特尔? 酷睿? i5 处理器智能特性，能够根据任务需求进行加速。英特尔? 酷睿? i5 处理器是一款出色的解决方案，适用于多媒体多任务处理环境。英特尔? 酷睿?2 至尊处理器适用于超级计算。享受英特尔最新双核及四核技术带来的革命性性能水准，获得逼真的高清晰度体验和多任务响应能力。英特尔? 酷睿?2 至尊处理器适用于超级计算。享受英特尔最新双核及四核技术带来的革命性性能水准，获得逼真的高清晰度体验和多任务响应能力。英特尔? 酷睿?2 四核处理器多媒体发烧友们将迎来一次疯狂的体验。借助英特尔? 酷睿?2 四核

处理器，为台式机带来强大的四核性能。它是高度线程化娱乐应用和高效多任务处理的理想引擎。英特尔? 酷睿?2 双核处理器至尊威力，铸就优异性能。凭借能效优化的双核技术和优异的能源使用效率，英特尔? 酷睿?2 双核处理器可以出色地运行要求最苛刻的应用程序。英特尔? 奔腾? 处理器英特尔? 奔腾? 处理器可提供超强的台式机性能、更低的能耗以及更出色的日常计算多任务处理能力。英特尔? 赛扬? 处理器基于英特尔? 赛扬? 处理器的台式机平台可为您提供超凡的计算体验，以及源自英特尔的出色品质和可靠性。 -------------------------------------------------------------------- 在同一处理器等级或家族内，编号越高表示特性越多，包括：高速缓存、时钟速度、前端总线、英特尔? 快速通道互联、新指令或其它英特尔技术1。拥有较高编号的处理器可能某一特性较强，而另一特性较弱。一、英特尔? 酷睿? 处理器英特尔? 酷睿? i7 品牌的处理器号由 i7 标识符加三字数字序列组成。

because,since,as,for的用法区别

because、since、as、for的用法区别 because、since、as、for这几个词都是表示“原因”的连词，语气由强至弱依次为：because→since→as→for。其中because、since和as均为从属连词，引导原因状语从句；而for是并列连词，引导并列句。 ?because because表示直接原因，它所指的原因通常是听话人所不知道的，其语气最强。常用来回答why的提问，一般放在主句之后，也可以单独存在例如： (1)Istayed at home because it rained. 因为下雨，我呆在家里。 (2)B ecause Lingling was ill, she didn’t come to school. 玲玲因为生病，没有上学。 (3)—Why is she absent? 她为什么缺席? —Because she is sick. 因为她病了。 (4)此外，在强调句型中只能用because。例如， It was because I missed the early bus that I was late for school. 我上学迟到是因为我错过了早班车。 ?since since侧重主句，从句表示显然的或已为人所知的理由，常译为“因为、既然”，语气比because稍弱，通常置于句首，表示一种含有勉强语气的原因。例如： (1)Si nce he asks you, you’ll tell him why. 他既然问你了，那就告诉他为什么吧。 (2)Si nce everyone is here, let’s start. 既然大家都到齐了，我们就是出发吧。 (3)Since I understood very little Japanese, I c ouldn’t follow the conversation. 我日语懂得不多，因而听不懂对话。 ?as as是常用词，它表示的“原因”是双方已知的事实或显而易见的原因，由于理由不是很重要，含义与since相同，但语气更弱，没有since正式，常译为“由于，鉴于”。从句说明原因，主句说明结果，主从并重。例如：

Intel处理器型号命名详解

Intel处理器型号命名详解　凭借着妇孺皆知的品牌效应和随处可见的广告宣传，Intel的CPU在国内拥有数量极其庞大的用户群。但是由于产品线频繁更新，别说是普通消费者，就连一些泡在卖场的商家都被其种类繁多的产品型号搅得一头雾水。下面笔者就将对这些CPU的型号命名进行讲解，以帮助读者选择自己钟意的产品。 Intel CPU产品介绍从大的命名规则来看，Intel的CPU产品主要分为Pentium奔腾系列和Celeron赛扬系列处理器。而从架构上区分，目前市面上的Intel CPU产品既有最常见的Socket 478架构，也有老一代的Socket 370架构，还有极少量的Socket 423架构。 (Intel的Pentium 4和Celeron处理器) 一、早期的Socket 370架构：这是Intel的早期产品，当前二手市场上能见到的有Coppermine铜矿核心的Pentium Ⅲ和Celeron Ⅱ，以及Tualatin图拉丁核心的Celeron Ⅲ。虽然看起来稍显过时，但其实这里面也有着性价比较高的产品。例如Tualatin图拉丁核心的Celeron Ⅲ，因为拥有 32KB的一级缓存和256KB的二级缓存，所以性能与同频的Pentium Ⅲ都有得一拼。并且由于采用了0.13微米制程，所以Tualatin图拉丁赛扬的超频潜力也不错。不过由于Intel的市场策略，Socket 370架构现已被彻底抛弃，基于该架构的主板和CPU产品也因此失去了任何升级潜力。所以这些CPU只适合老用户升级使用，并不推荐新装机的用户购买。二、过渡型Socket 423架构：这主要见于Intel第一批推出的Willamette核心Pentium 4产品。但它只不过是昙花一现，上市不久便立即被Socket 478架构所取代。其相应的处理器和主板产品也迅速被品牌机等市场消化，现在市场上已经几乎见不到它们了。所以如果您在逛市场时见到这样的CPU，估计都是不知道从哪翻出的仓底货或是二手产品，笔者奉劝大家尽量少碰为妙。三、主流的Socket 478架构：这是当前Intel的主流产品，产品线中既包括有高端的Pentium 4处理器，也包括了低端的Celeron处理器。可就是同属Socket 478架构的Intel处理器，也有许多不同类型。这就是我们下面将要讲述的内容。 "ABCDE"含义释疑我们知道，Intel的不少Pentium 4处理器在频率后面还带有一个字母后缀，不同的字母也代表了不同的含义。 "A"的含义： Pentium 4处理器有Willamette、Northwood和Prescott三种不同核心。其中Willamette核心属于最早期的产品，采用0.18微米工艺制造。因为它发热较大、频率提升困难，而且二级缓存只有256KB，所以性能颇不理想。于是Intel很快用Northwood核心取代了它的位置。Northwood核心Pentium 4采用0.13微米制程，主频有了很大的飞跃，二级缓存容量也翻了一番达到了512KB。为了与频率相同但只有256KB二级缓存的Pentium 4产品区别，Intel在其型号后面加了一个大写字母"A"，例如"P4 1.8A"，代表产品拥有 512KB二级缓存。这些产品均只有400MHz的前端总线(Front Side Bus，简称FSB)。"B"的含义：同样频率的产品，在更高的外频下可具备更高的前端总线，因此性能也更高。为此Intel在提升CPU频率的同时，也在不断提高产品的前端总线。于是从可以支持533MHz FSB的845E等主板上市开始，市场上又出现了533MHz FSB的Pentium 4处理器。为了与主频相同但是只有400MHz FSB的Pentium 4产品区别开来，Intel又给它们加上了字母"B"作为后缀，例如"P4 2.4B"。 "C"的含义：

because, since, as与for用法辨析

because, since, as与for用法辨析 1. because的用法 because语气最强，表示直接原因，可用于回答 why 提出的问题、引导表语从句、用于强调句等，而其余三者均不行。如： A：Why didn’t she come? 她为什么没来? B：Because she was very busy. 因为她很忙。 It is because he is clever that I like him. 是因为他聪明我才喜欢他。 2. since与as 两者所表示的原因都是人们已知的，即对已知事实提供理由，而不是表示直接原因。since 比 as 语气稍强，且比 as 略为正式，它们引导的从句通常放在主句之前，有时也放在主句之后。如： As you weren’t there, I left a message. 由于你不在那儿，我留了个口信。 Since you’ve been here a w hile, you might as well stay. 既然你已经来了一段时间，就不妨继续待下去。另外，since 可用于省略句，而其他三者不行。如： Since so, I have nothing to say. 既然如此，我无话可说。 3. for的用法

for是并列连词，而其余三者为从属连词。for有时可表示因果关系(通常要放在主句之后，且可与 because 换用)；有时不表示因果关系，而是对前面分句内容的解释或推断(也要放在主句之后，但不能与because 换用)。比较： The ground is wet，for (＝because) it rained last night. 地面是湿的，因为昨晚下过雨。 It must have rained last night，for the ground is wet this morning. 昨晚一定下过雨，你看今天早上地面是湿的。 (此句不能用 because 代 for) 英语微信群是目前学习英语最有效的方法，群里都是说英语，没有半个中文，而且规则非常严格，是一个超级不错的英语学习环境，群里有好多英语超好的超牛逼的人，还有鬼佬和外国美眉。其实坦白说，如果自己一个人学习英语太孤独，太寂寞，没有办法坚持，好几次都会半途而废。只要你加入到那个群里以后，自己就会每天都能在群里坚持学，坚持不停地说和练，由于是付费群，群里的成员学习氛围非常强，每天的训练度都非常猛，本来很懒惰的你一下子就被感染了，不由自主地被带动起来参与操练，不好意思偷懒，别人的刻苦学习精神会不知不觉影响你，EYC英语微信群（群主vx 601332975）可以彻底治好你的拖延症，里面学员都非常友好，总是给你不断的帮助和鼓励，让你学英语的路上重新燃起了斗志，因为每天都在运用，你的英语口语就能得到了迅猛的提升，现在可以随便给一个话题，都能用英文滔滔不绝的发表5分钟以上对这个话题的看法和观点，想提高英语口语的可以加入进来，It really works very well.

大学英语四级基础复习讲义.pdf

plete 指完成一件指派或预定的任务,或完善、完整未完成的部分 gain 指需要做出比 obtain 更大的努力,往往指通过竞争获得某些有价值的东西obtain 指经过努力或付出代价或经过很长时间儿得到所需要的东西end 指一个动作或一件事情的结束或终止 finish 指把一件事或一个动作做完,强调事情的了结、终止 7、4 、 accurate , correct , delicate , exact,precise 都含有一定的"正确,精确" 之意 acknowledge,admit,concede,confess,rec ognize 都含有一定的"承认"之意acknowledge 着重”公开承认”,常用来指过去曾隐瞒或否认的事accurate 准确的,精确的,指某人或某事不仅不出错,而且与事实无出入,强调准确性 admit 是指在压力下不得不承认已经证实或难以否认的事实,招供(事实,错误等)concede(不情愿地)承认,(在结果确定前)承认失败correct 正确的,指某人或某事合乎事实或公认的标准或规则,没有错误 delicate 精美、精细的、雅致的 exact 确切的、精确的,语气较 accurate 强, 指某人或某事数量或质量完全符合事实或标准,而且在细致末节上也丝毫不差 precise 精密的,指具有高度的精确性和准确性,强调范围界限的鲜明性或细节的精密, 有时略带"吹毛求疵"的贬义 confess 着重承认自己的过错或罪恶recognize 指正式承认主权、权利等8、affirm,assert,allege,claim 都含有一定的"宣称,断言"之意affirm 断言,肯定,指根据事实坚定不移地宣称,有无可争辩之意assert 宣称,坚持,指不管事实如何,主观自信地宣称5、accuse,charge,indict 都含有一定的 "指控,控告"之意 allege 宣称,断定,指在无真实根据情况下宣称,硬说accuseaccusesb.ofdoingsth. 为 … 指责某人,控告某人 claim 声称,主张,往往表示说话者反对或不同意某一观点chargechargesb.withdoingsth. 指控某人… 英语四级温习资料 2(2006-12-1116:02:10)分类：大学英语四六级温习资料征服大学英语四级考试（阅读篇）（一）存在问题6、achieve,acquire,attain,gain,obtain 都含有一定的"获得,达到"之意 achieve 强调由于极大的努力,克服困难后达到目标第一,读不懂acquire 指经过不懈努力才获得的技术,知识等抽象的东西,也指养成习惯等 attain 正式用语,指经过艰苦努力才使人达到完美境地所谓读不懂,就是考生拿过文章,满头雾水,即使硬着头皮读文章,也是一知半解。然后匆忙做体,仅凭感觉去蒙,因此做体准确率必然不高。

英特尔全线处理器型号及参数总览表

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Intel_CPU型号规格大全

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while、when和as的用法区别

as when while 的区别和用法 as when while的用法一、as的意思是“正当……时候”,它既可表示一个具体的时间点，也可以表示一段时间。as可表示主句和从句的动作同时发生或同时持续，即“点点重合”“线线重合”；又可表示一个动作发生在另一个动作的持续过程中，即“点线重合”，但不能表示两个动作一前一后发生。如果主句和从句的谓语动词都表示持续性的动作，二者均可用进行时，也可以一个用进行时，一个用一般时或者都用一般时。 1、As I got on the bus，he got off. 我上车，他下车。（点点重合）两个动作都是非延续性的 2、He was writing as I was reading. 我看书时，他在写字。（线线重合）两个动作都是延续性的 3、The students were talking as the teacher came in. 老师进来时，学生们正在讲话。（点线重合）前一个动作是延续性的，而后一个动作时非延续性的二、while的意思是“在……同时（at the same time that )”“在……期间(for as long as, during the time that）”。从while的本身词义来看，它只能表示一段时间，不能表示具体的时间点。在时间上可以是“线线重合”或“点线重合”，但不能表示“点点重合”。例如： 1、He was watching TV while she was cooking. 她做饭时，他在看电视。（线线重合） 2、He was waiting for me while I was working. 我工作的时候，他正等着我。（线线重合） 3、He asked me a question while I was speaking. 我在讲话时，他问了我一个问题。（点线重合）

Cpu型号大全及其参数

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工作功率：45W ￥1979Intel 酷睿i7-3770 CPU频率：3.4GHz CPU核心：四核接口类型：LGA 1155 制程工艺：22纳米三级缓存：8MB 工作功率：77W CPU说明：Intel Core i7-3770... 睿频加速频率：3.9 ￥1239Intel 酷睿i5 3470(散) CPU频率：3.2GHz CPU核心：四核接口类型：LGA 1155 制程工艺：22纳米三级缓存：6MB 核心类型：ivy bridge 工作功率：77W 加入对比￥1239Intel 酷睿i5 3470(盒) CPU频率：3.2GHz CPU核心：四核接口类型：LGA 1155 制程工艺：22纳米三级缓存：6MB 核心类型：ivy bridge 工作功率：77W CPU说明：Intel 酷睿i5 3470 ..

intel cpu型号大全

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高中英语as用法全归纳

高中英语a s用法全归纳 Revised on November 25, 2020

高中英语as用法全归纳 as的用法灵活，词义繁多，特别是在复合句中更能体现其用法的多样性和灵活性，但如果同学们能正确掌握as的词性和词义，是不难掌握其用法的。一、as用作关系代词引导定语从句

引导非限制性定语从句，一般不指代某个具体的名词或代词，而是代表整个主句或主句的一部分。这种从句可放在主句之前，也可以放在主句之后，有时还可以放在主句的中间。如： Asisreportedinthenew spapers,talksbetweenthetw ocountriesaremakingprogr ess.正如在报纸上所报道

的，两国间的谈判有所进展。 Grammarisnotasetofd eadrules,ashasbeensaidabo ve.如上所说，语法不是一套死条文。 Spidersarenotinsects, asmanypeoplethink,noreve nnearlyrelatedtothem.蜘蛛不是昆虫，尽管许多人都这样认为，它甚至与昆虫几乎没有联系。

引导限制性定语从句，主要用于thesame…as（与……相同），such…as（像……一样），as…as（与……一样）。如： Sheknewhefeltjustthe sameasshedid.她知道他的感受和她一样。 .像李先生这样好脾气的人是容易相处的。

Hesmokesasexpensive acigaretteashecanafford.他抽一种他买得起的最贵的烟。二、as作为从属连词引导时间状语从句表示“随着……”或者“当……的时候”或“一边……一边”，强调主句的动作和从句的动作同时发生。如：

because,since,as,for的用法辨析

because, since, as, for的用法辨析一、because的用法语气最强，表示直接原因，可用于回答why 提出的问题、引导表语从句、用于强调句等，而其余三者均不行。如： A：Why didn’t he come? 他为什么没来? B：Because he was ill. 因为他病了。 It is because he is too busy. 那是因为他太忙了。 It is because he is honest that I like him. 是因为他诚实我才喜欢他。二、since 与as的用法 (1) 两者所表示的原因都是人们已知的，即对已知事实提供理由，而不是表示直接原因。since 比as 语气稍强，且比as 略为正式，它们引导的从句通常放在主句之前，有时也放在主句之后。如： As you weren’t there, I left a message. 由于你不在那儿，我留了个口信。 Since you are wrong, you should apologize. 你既然错了，就应该道歉。 (2) since 可用于省略句，而其他三者不行。如： Since so, I have nothing to say. 既然如此，我无话可说。三、for的用法是并列连词(其余三者为从属连词)，它有时可表示因果关系(通常要放在主句之后，且可与because 换用)；有时不表示因果关系，而是对前面分句内容的解释或推断(也要放在主句之后，但不能与because 换用)。比较： The ground is wet，for (＝because) it rained last night. 地面是湿的，因为昨晚下过雨。 It must have rained last night，for the ground is wet this morning. 昨晚一定下过雨，你看今天早上地面是湿的。(此句不能用because 代for) 四、惯用法方法区别汉语习惯上说“因为……所以……”，但是在英语里却不能将so 与because, since, as 等连用：因为天气很好，所以我们去游泳了。误：Because it was fine, so we went swimming. 正：Because it was fine, we went swimming. 正：It was fine, so we went swimming. 因为很迟了，所以我要回家了。误：Since it is late, so I shall go home now. 正：Since it is late, I shall go home now.

CPU品牌型号及Intel命名规则

Center Process Unit中央处理器,由运算器和控制器组成。 CPU厂商会根据CPU产品的市场定位来给属于同一系列的CPU产品确定一个系列型号以便于分类和管理，一般而言系列型号可以说是用于区分CPU性能的重要标识。早期的CPU系列型号并没有明显的高低端之分，例如Intel的面向主流桌面市场的Pentium和Pentium MMX以及面向高端服务器生产的Pentium Pro；AMD的面向主流桌面市场的K5、K6、K6-2和K6-III以及面向移动市场的K6-2+和K6-III+等等。随着CPU技术和IT市场的发展，Intel和AMD两大CPU生产厂商出于细分市场的目的，都不约而同的将自己旗下的CPU产品细分为高低端，从而以性能高低来细分市场。而高低端CPU系列型号之间的区别无非就是二级缓存容量(一般都只具有高端产品的四分之一)、外频、前端总线频率、支持的指令集以及支持的特殊技术等几个重要方面，基本上可以认为低端CPU产品就是高端CPU产品的缩水版。例如Intel方面的Celeron系列除了最初的产品没有二级缓存之外，就始终只具有128KB的二级缓存和66MHz以及100MHz的外频，比同时代的Pentium II/III/4系列都要差得多，而AMD方面的Duron也始终只具有64KB 的二级缓存，外频也始终要比同时代的Athlon和Athlon XP要低一个数量级。 CPU系列划分为高低端之后，两大CPU厂商分别都推出了自己的一系列产品。在桌面平台方面，有Intel面向主流桌面市场的Pentium II、Pentium III 和Pentium 4以及面向低端桌面市场的Celeron系列(包括俗称的I/II/III/IV 代)；而AMD方面则有面向主流桌面市场Athlon、Athlon XP以及面向低端桌面市场的Duron和Sempron等等。在移动平台方面，Intel则有面向高端移动市场的Mobile Pentium II、Mobile Pentium III、Mobile Pentium 4-M、Mobile Pentium 4和Pentium M以及面向低端移动市场的Mobile Celeron和Celeron M；AMD方面也有面向高端移动市场的Mobile Athlon 4、Mobile Athlon XP-M和Mobile Athlon 64以及面向低端移动市场的Mobile Duron和Mobile Sempron 等等。目前，CPU的系列型号更是被进一步细分为高中低三种类型。就以台式机CPU而言，Intel方面，高端的是双核心的Pentium EE以及单核心的Pentium 4 EE，中端的是双核心的Pentium D和单核心的Pentium 4，低端的则是Celeron D以及已经被淘汰掉的Celeron(即俗称的Celeron IV)；而AMD方面，高端的是Athlon 64 FX(包括单核心和双核心)，中端的则是双核心的Athlon 64 X2 和单核心的Athlon 64，低端就是Sempron。以笔记本CPU而言，Intel方面高端的是Core Duo，中端的是Core Solo和即将被淘汰的Pentium M，低端的则是Celeron M；而AMD方面，高端的则是Turion 64，中端的是Mobile Athlon 64，低端的则是Mobile Sempron。但在购买CPU产品时需要注意的是，以系列型号来区分CPU性能的高低也只对同时期的产品才有效，任何事物都是相对的，今天的高端就是明天的中端、