Detection of inflammatory bowel disease : diagnostic performance of cross-sectional imaging modalities Different cross-sectional imaging techniques can be used as a diagnostic tool for the evaluation of inflammatory bowel disease -LRB- IBD -RRB- . In this report the diagnostic performances of ultrasonography , magnetic resonance imaging and computed tomography in the detection of IBD and the evaluation of known IBD are described , together with a short update on patient preparation and imaging technique of the respective modalities discussed . Introduction Chronic inflammatory bowel disease -LRB- IBD -RRB- consists of two main subtypes , i.e. , Crohn 's disease -LRB- CD -RRB- and ulcerative colitis -LRB- UC -RRB- . During the last decades , the incidence of CD has continued to increase worldwide , reaching incidence rates ranging from 3.1 to 14.6 / 100,000 in North America and from 0.7 to 9.8 / 100,000 in Europe -LSB- 1 -RSB- . Incidence rates of UC differ greatly between studies and regions , varying from 1.5 to 24.5 per 100,000 person-years -LSB- 1 , 2 -RSB- . Crohn 's disease can be localized in any part of the gastrointestinal tract , although the location of predilection is the terminal ileum , involvement of the terminal ileum is observed in 90 % of the patients with small-intestinal CD , who in turn constitute 30 -- 40 % of all CD patients . In 40 -- 55 % of the patients both ileum and colon are affected , while in a minority -LRB- 15 -- 25 % -RRB- only a colonic localization is observed . The earliest change caused by CD occurs in the mucosa and submucosa and consists of hyperemia and edema . Tiny aphthoid or superficial ulcerations can be seen when disease progresses . In more severe disease , the disease extends transmurally with sometimes serosal involvement . In this stage , mucosal ulcerations merge to form deep longitudinal and transverse ulcerations while bowel wall thickening and narrowing of the bowel lumen can be observed due to significant mucosal edema and associated bowel spasms . In long-standing disease , chronic obstruction can develop due to scarring , luminal narrowing , and stricture formation . Extramural manifestations of CD are fistulas , abscesses , adhesions , creeping fat , and enlargement of lymph nodes . Ulcerative colitis exclusively affects the colon with a predictable way of spreading from distal to proximal in a continuous manner ; the rectum is often involved , but rectal sparing can be observed . In previous cases , small superficial erosions can be seen , whereas in more severe disease these ulcerations can be quite large . However , only in very severe disease they penetrate the muscularis layer . The mucosa is thickened because of round-cell infiltration in the lamina propria . In chronic UC , a marked hypertrophy of muscularis mucosae can be seen , causing contraction , shortening , and narrowing of the involved colon . The submucosa becomes thickened because of the deposition of fat or , in acute or subacute cases , edema -LSB- 3 , 4 -RSB- . Diagnostic modalities The gold standard examination for the small bowel traditionally has been small bowel barium examination -LRB- SBE -RRB- , either by using an enteroclysis technique or by using small-bowel follow-through -LSB- 5 , 6 -RSB- . SBE is invasive and burdensome , and requires an extensive bowel preparation -LRB- dietary restrictions , use of laxatives -RRB- . Moreover , in the young population of CD patients , the ionizing radiation required for SBE limits the use of this technique for follow-up of disease . The advent of video capsule endoscopy -LRB- VCE -RRB- and double-balloon endoscopy -LRB- DBE -RRB- has increased the diagnostic possibilities . For VCE a capsule is swallowed after a fasting period of up to 12 h and is propelled through the bowel by peristalsis . Thus , the mucosal surface of the small bowel can be depicted in detail -LRB- Fig. 1 -RRB- . However , with VCE there is no facility to increase visibility by insufflation of air or by tissue rinsing . Moreover , tissue sampling and therapeutic interventions are not possible . The use of VCE is contraindicated in patients with -LRB- suspicion of -RRB- obstruction due to the risk of capsule retention . Fig. 1 . VCE image of a 14-year-old male patient with known CD . VCE was performed as small-bowel disease was suspected . Image shows severe inflammation of the small bowel with a stenosis . For DBE , a high-resolution video-endoscope with a flexible overtube is used . By alternately inflating and deflating two balloons attached to the overtube and endoscope the small bowel is threaded on the overtube . Both an oral and an anal approach are possible ; for the oral approach no specific preparation is required , although patients are asked to fast for at least 6 h before the procedure . If the anal approach is used , bowel cleansing such as is employed for traditional colonoscopy is used . By using both the anal and oral approach , DBE allows visualization of the entire small bowel , with the possibility of obtaining tissue for analysis and the added advantage of the possibility of endoscopic therapy -LRB- e.g. dilatation of a stricture , cauterization of a bleeding site -RRB- . For DBE conscious sedation is a necessity . Traditionally , ileocolonoscopy -LRB- CS -RRB- with tissue sampling is considered to be the most valuable tool for diagnosis and follow-up of disease in the colon and terminal ileum -LSB- 5 , 7 -RSB- . As UC solely affects the mucosa of the colon , CS would suffice for diagnosis of disease and evaluation of disease activity and extent . However , when strictures are present as a complication of disease , these might hamper execution of a complete examination , while in severe attacks of UC CS is relatively contra-indicated due to the increased risk of bleeding or perforation . For ileocolonic localizations of CD CS would suffice as well , although inspection of the terminal ileum is reported to fail in up to 27.8 % of examinations -LSB- 8 , 9 -RSB- . Cross-sectional imaging modalities The trans - and extramural extent of IBD can not be visualized with any of the abovementioned techniques . Much research has been directed toward the potential of cross-sectional imaging modalities for the diagnosis and evaluation of IBD as with these techniques the bowel lumen , the bowel wall and the extra-intestinal abdomen including the visceral fat , the lymph nodes and the vascular structures feeding and draining the bowel can be visualized . An added advantage of these techniques is the fact that they are limitedly to non-invasive . Ultrasonography -LRB- US -RRB- , computed tomography -LRB- CT -RRB- and magnetic resonance imaging -LRB- MRI -RRB- are often used for the evaluation of the abdomen . While in the USA the technique of choice is CT , in Europe the focus is more on MRI and US . This inclination is reflected by the majority of CT studies on IBD patients originating from the USA , while the majority of published studies on MRI and US has been conducted in Europe . Ultrasonography Patient preparation and US technique Patients are usually asked to fast for several hours before the scan to diminish peristaltic movements and the amount of intraluminal air ; in the available literature the minimum fasting time described is 4 h , whereas overnight fasting is also sometimes employed . Usually , no additional dietary or cleansing measures are taken . Due to the limited patient preparation necessary and the non-invasive nature of this examination , US can be considered to be a relatively patient-friendly and straightforward examination . Ultrasonography is mostly performed without the use of enteral contrast medium . In two recent studies , the effect of enteral contrast medium for diagnosis of IBD of the small bowel was investigated ; higher sensitivity values were obtained when enteral contrast medium had been administered -LSB- 10 , 11 -RSB- . In both studies the additional value of enteral contrast medium permitted detection of jejunal lesions that had escaped detection with conventional US . For colonic IBD , use of enteral contrast medium also increased accuracy -LSB- 12 , 13 -RSB- . High-frequency transducers are preferred , such as 7.5 MHz -LSB- 13 -- 16 -RSB- . The use of Doppler-US might provide helpful additional information on IBD , particularly on the degree of disease activity . Using Doppler-US the vascularity of the bowel wall can be assessed according to the intensity of color signals and/or by the analysis of Doppler curves -LRB- measurement of resistive index -RRB- obtained from vessels detected within the bowel wall . Measurement of flow parameters of the superior and inferior mesenteric arteries can also be performed . Imaging criteria The criterion that is most extensively used for the diagnosis of CD is bowel wall thickening . In most studies , the bowel wall is considered to be thickened when thickness exceeds 3 mm -LRB- Fig. 2 -RRB- . In a meta-analysis conducted by Fraquelli et al. -LSB- 17 -RSB- concerning US in CD the respective diagnostic accuracies of different cut-off values were compared ; sensitivity for diagnosis of CD decreased using a cut-off value of 4 mm instead of 3 mm -LRB- from 88 % to 75 % -RRB- , but specificity increased slightly -LRB- from 93 % to 97 % -RRB- . Other features that are considered characteristic of CD on US are the presence of a stiff bowel wall , modification or disappearance of bowel wall stratification , presence of deep ulcers -LRB- seen as interruption of the submucosal hyperechoic rim by a hypoechoic tract -RRB- , a reduction of peristalsis and loss of haustration in the colon . Extramural findings are fibrofatty proliferation , enlarged lymph nodes , and/or the presence of an abscess or fistula . Fig. 2 . A 14-year female patient with known CD and intermittent abdominal pain . US image shows the thickened wall of the terminal ileum -LRB- arrowheads -RRB- with some infiltration of the perivisceral fat . Bowel wall thickening is considered to be a characteristic feature of UC as well . Mural stratification is preserved in most UC patients due to the superficial pattern of inflammation . This feature can be used to differentiate between CD and UC , although this was not regarded sufficient for differentiation in all studies on this topic -LSB- 12 , 13 -RSB- . In long-standing UC a tubular appearance of the colon and loss of haustration can be seen . Diagnostic accuracy of US Most studies regarding diagnostic accuracy of US for diagnosis and follow-up of IBD have been conducted in the last decade . Although reported sensitivity and specificity values are high , with the state-of-the-art equipment diagnostic accuracy could possibly be higher than that previously reported . In the hands of an experienced radiologist , US can be very accurate for the detection of IBD . Reported sensitivity values of US for the detection of IBD in patients with suspected disease vary from 76 % to 92 % -LSB- 15 , 18 , 19 -RSB- ; specificity values are also high . In patients with proven IBD , reported sensitivity values for US are higher , probably reflecting a higher index of suspicion -LSB- 10 , 20 -RSB- . Reported segmental sensitivity values are lower ; these are below 78 % , even if gray-scale US is combined with power Doppler -LSB- 21 , 22 -RSB- . Regarding the detection of extramural complications , fistulas and abscesses can be identified accurately on US -LSB- 23 , 24 -RSB- -LRB- Fig. 3 -RRB- . Fig. 3 . A 25-year-old female patient with known CD of the terminal ileum . A US image shows a large abscess -LRB- arrowheads -RRB- that was located ventrally and cranially of the bladder . B US image shows a fistula -LRB- arrowheads -RRB- that originated from the abscess . Although many US studies have been carried out , most concerned either CD patients or both CD and UC patients , and reported accuracy values are usually applicable for both subgroups of disease . Although in the study by Limberg and Osswald -LSB- 13 -RSB- separate accuracy values are provided for US and CD , it is not clear from these data if accuracy values were obtained from post hoc separation of data . To our knowledge , as of yet no prospective study has been performed with predetermined imaging parameters to differentiate between CD and UC . Although US can be used for the assessment of both small bowel and colon , disease localized in the duodenum and jejunum is often missed -LSB- 18 , 19 , 25 -RSB- . Moreover , the rectum and distal sigmoid can not be visualized accurately due to their pelvic location . This makes US less suitable for the assessment of UC . Doppler US has been proved useful in assessing whether IBD is in an active phase or in remission ; significant correlations were found between Doppler parameters and disease activity , both in UC -LSB- 26 -RSB- and in CD -LSB- 27 -RSB- . However , the only distinction made was between active and inactive disease , meaning no conclusions can be drawn about the severity of active disease from these data . As of yet , there is no standardized scale to determine the degree of disease activity on US , neither for CD nor for UC . The spatial resolution of US is not high enough to permit the detection of superficial pathology , making this modality less suitable for the diagnosis of early diseases when compared with SBE . Although SBE can reportedly be highly accurate when performed by skilled radiologists -LSB- 28 , 29 -RSB- , compared with VCE or DBE its sensitivity is low -LSB- 30 -RSB- . In this regard , comparison between US and VCE and/or DBE might be very interesting in order to determine the accuracy of US for small lesions and accuracy for bowel segments that are difficult to access . To our knowledge , no comparative studies have been performed as of yet . Computed tomography Patient preparation Patients are usually asked to fast for several hours before the scan to diminish peristaltic movements -LSB- 31 -- 33 -RSB- . In addition , in some institutions a bowel-cleansing regimen is applied , as a rule consisting of mild laxatives . Dietary restrictions are also often applicable . Although with this bowel preparation residual feces are usually present to some degree , the mural presentation of disease enables the identification of disease even if the bowel wall is partly obscured . There is consensus as to the indispensability of enteral contrast medium for an abdominal CT examination for IBD . The contrast medium of choice should be neutral -LRB- meaning an attenuation value comparable with water -RRB- , as a neutral contrast medium allows optimal distinction between bowel wall and lumen . While in some institutions enteral contrast medium is administered orally -LRB- CT enterography -RRB- , in other institutions controlled distention is achieved by inflow of contrast medium through a nasojejunal catheter -LRB- CT-enteroclysis -RRB- . Although by some authors CT-enteroclysis is propagated as the controlled infusion provides a more consistent distention of the small bowel than CT-enterography , especially of the jejunum -LSB- 34 -RSB- , others report that with the right choice of contrast medium and correct timing of intake excellent distention of all small bowel loops can be obtained after the oral administration of contrast medium -LSB- 31 , 33 -RSB- . In only one small study , CT enteroclysis and CT enterography were compared , but both the degree of luminal distention and the diagnostic accuracy did not show significant differences -LSB- 35 -RSB- . Imaging technique Technical developments have allowed the widespread use of multi-slice scanners . With these scanners volumes can be scanned in a very short breath hold , allowing the acquisition of isotropic voxels for multiplanar reformatting . Thin slices should be used to permit the detection of subtle pathology . Before CT enterography sometimes metoclopramide is given to increase gastric emptying and peristaltic movements of the small bowel -LSB- 31 -RSB- . The use of antiperistaltic drugs is not standard . In a recently published update on CT enteroclysis , Rajesh and Maglinte -LSB- 32 -RSB- report that in their institution all patients undergoing CT enteroclysis receive conscious sedation . Although this most probably decreases patient discomfort to a large degree , this can considerably increase the in-hospital time for patients as they will have to stay in a recovery unit after the procedure until the anesthetic effects have worn off . Intravenous contrast medium should be administered for a comprehensive CT examination of the bowel . In a recent study , the optimal timing of scanning after the administration of intravenous contrast medium was determined ; Schindera et al. -LSB- 36 -RSB- found that peak mural enhancement of normal small-bowel wall occurs on average about 50 s after contrast administration or 14 s after peak aortic enhancement . Imaging criteria The main feature considered indicative of both CD and UC is bowel wall thickening . Whereas in earlier studies cut-off values for pathological bowel wall thickening have varied between 2.5 mm and 10 mm , in recent publications of experts in the field bowel wall thickness exceeding 3 mm is described as pathological -LSB- 31 , 33 -RSB- -LRB- Fig. 4 -RRB- . Mural thickening is not seen in early superficial disease , precluding CT from being a first-line examination for -LRB- suspicion of -RRB- superficial disease . Fig. 4 . A 60-year old female patient who underwent CT enterography for suspected bowel obstruction . Just 1 month earlier at ileocolonoscopy CD of the terminal ileum was discovered ; the terminal ileum was not intubated because of the stenosis . Axial image shows the severely thickened bowel wall of the ileum -LRB- arrowheads -RRB- with only a pinpoint bowel lumen remaining . Increased bowel wall enhancement after the administration of intravenous contrast medium is also considered as an indicative of active disease -LSB- 37 -- 39 -RSB- . Whereas in earlier studies the only distinction regarding enhancement was between pathological enhancement -LRB- i.e. , hyper-enhancement -RRB- and normally enhancing bowel walls , in a recent publication the degree of mural enhancement was found to correlate with disease activity -LSB- 38 -RSB- . Bowel wall enhancement can be transmural , but also layered . This layered enhancement pattern , which is represented by a thickened intestinal wall with a middle layer of low attenuation surrounded on each side by layers of higher attenuation , has been termed the target sign ; this is due to the presence of edema or the deposition of fat in the submucosa . Diagnostic accuracy of CT The accuracy of CT has mainly been investigated for small-bowel disease . In suspected CD sensitivity was 83 % when compared with SBE -LSB- 40 -RSB- . When compared with ileoscopy sensitivity values vary from 80 % to 88 % -LSB- 34 , 35 , 41 -RSB- . Segmental sensitivity of CT was somewhat lower -LRB- 71.8 % -RRB- in a study by Molnar et al. -LSB- 42 -RSB- , comparing CT with SBE and CS . Superficial lesions -LRB- such as aphthoid lesions -RRB- are not accurately visualized on CT , making CT less suitable as a first-line examination for the suspicion of mild disease . This was already evident from studies comparing CT with CS and/or SBE , but in a recent meta-analysis comparing CT with VCE was shown that the yield of CT compared with the yield of CE was 30 % vs. 69 % -LSB- 43 -RSB- . No comparative studies have been published regarding CT vs. DBE . Extramural complications are well shown on CT , although the lower contrast resolution of CT makes this modality less suitable for the detection of fistulas and abscesses than MRI in patients with CD -LSB- 44 -RSB- -LRB- Fig. 5 -RRB- . In a recent study , the relationship between increased attenuation of perivisceral fat and disease activity was determined ; one of the most specific markers of active disease was increased attenuation in the perivisceral fat -LSB- 37 -RSB- . Fig. 5 . A 25-year-old female patient with known CD of the terminal ileum -LRB- same patient as pictured in Fig. 3 -RRB- . A CT-scan was performed to determine involvement of the small bowel . A Coronal image shows the abscess -LRB- arrowheads -RRB- . B Axial image again shows the abscess again -LRB- arrowheads -RRB- . C Coronal image shows the fistula -LRB- arrowhead -RRB- . Hardly any studies have focused on the accuracy of CT colonography for the detection of ileocolonic IBD . This is possibly partly due to the fact that for the rectal administration of contrast medium the rectum is obscured by the rectal catheter , precluding diagnosis of rectal IBD , specifically UC . It does seem clear that CTC is unable to detect ulcerative lesions ; even diffuse inflammation with large ulcerations can be missed . CTC might however be useful in patients with colonic stenosis or narrowing -LSB- 45 , 46 -RSB- . Magnetic resonance imaging Patient preparation While in some studies on MRI a period of several hours of fasting was deemed sufficient , in others full bowel cleansing was performed , as the reference standard , -LRB- i.e. , CS -RRB- was performed on the same day . There is no consensus yet as to what constitutes the optimal bowel preparation for MRI . However , as a limited bowel preparation does not seem to negatively affect accuracy , it might be sufficient to limit the bowel preparation to a fasting period taking into account the patient-friendliness of the respective preparations . Luminal distention by means of use of enteral contrast medium is indispensable for an adequate evaluation of the bowel as collapsed bowel can hide or mimic disease . As was the case with CT , for MRI of the small bowel contrast medium is either administrated by mouth or by enteroclysis . An advantage of MR enteroclysis over MR enterography is the fact that it allows fluoroscopic monitoring of the inflow of contrast medium and thereby provides functional information on bowel distensibility . An advantage of MR enterography is the fact that it can be considered more patient-friendly and also that no ionizing radiation is necessary . To our knowledge , only one study has been carried out in which both methods of contrast medium administration were compared . In this study by Schreyer et al. -LSB- 47 -RSB- all patients -LRB- n = 21 -RRB- underwent both MRI enterography and MRI enteroclysis ; no difference in accuracy compared with SBE was noted by the investigators -LRB- Fig. 6 -RRB- . Fig. 6 . A A 38-year-old female with complaints of vomiting and an iron-deficiency anemia who was suspected of CD and underwent MRI-enteroclysis to evaluate the small bowel . Coronal TrueFISP image shows good distention of jejunal bowel loops after controlled infusion of contrast medium . B A 12-year-old male patient with known CD who underwent MR enterography for the evaluation of the small bowel . Coronal TrueFISP image shows good distention of jejunal bowel loops after oral administration of contrast medium . Whereas for MR enteroclysis mostly a methylcellulose suspension is used , for MR enterography many different contrast media have been tested . The main subdivision is between positive , negative , and biphasic contrast media . A biphasic contrast medium performs best for the identification of pathology on both T2-and T1-weighted sequences as adequate delineation between hypointense bowel wall and hyperintense lumen is seen on T2-weighted sequences while on T1-weighted images the enhancing bowel wall can be easily discriminated from the hypointense lumen . An artificial sugar-solution -LRB- mannitol or sorbitol -RRB- has been shown to cause good distention of small bowel loops with negligible side effects -LSB- 48 , 49 -RSB- . Imaging technique Mostly , both T2-weighted and T1-weighted sequences are used for the MRI evaluation of the bowel . On T2-weighted images the bowel wall can be appreciated and bowel wall stratification -- if present -- can be well apprehended . As feces can show bright signal intensity on T1-weighted sequences , it is important to perform a pre-contrast T1-weighted sequence in order to be able to determine whether high signal intensity was already present before intravenous contrast administration , indicating the presence of stool . Another sequence that is propagated by many authors is the TrueFISp sequence , a sequence that is insensitive to motion and breathing artifacts . This sequence , that makes use of a T2/T1 ratio , adequately delineates the bowel wall and the mesentery , allowing adequate assessment of disease -LRB- Fig. 7 -RRB- . When combining a T2-weighted sequence or TrueFISP sequence and a T1-weighted sequence , a comprehensive MRI examination can be carried out in less than 30 min . Fig. 7 . A 18-year-old female patient with known CD . MRI-enterography was performed for suspicion of active CD of the neoterminal ileum . A Coronal TrueFISp image shows enlarged mesenteric lymph nodes -LRB- arrowheads -RRB- . B Coronal TrueFISP image shows thickened bowel wall of the neoterminal ileum -LRB- arrowheads -RRB- . Imaging criteria A bowel wall thickness exceeding 3 mm should be considered as an indicative of disease . Besides bowel wall thickening the most important criterion indicative of active IBD is pathological bowel wall enhancement after the administration of intravenous gadolinium . Bowel wall enhancement can always be seen as the bowel is a highly vascularized structure . However , in active IBD increased enhancement can be observed , due to the increased vascularization and the increased capillary leakage of the affected tissue -LRB- Fig. 8 -RRB- . In CD it has been hypothesized that the degree of enhancement correlates with the degree of disease severity , but this statement has not been extensively corroborated -LSB- 50 -- 53 -RSB- . Fig. 8 . A 12-year-old male patient with known CD who underwent MR-enterography for the evaluation of the small bowel -LRB- same patient depicted in Fig. 6b -RRB- . Axial T1-weighted image shows pathological enhancement of thickened small-bowel loops after administration of intravenous contrast medium -LRB- arrowheads -RRB- . Approximately , 1 m of small bowel -LRB- terminal jejunum , proximal ileum -RRB- was shown to be affected . Bowel wall stratification can be observed on T2-weighted images as a bright line within the two dark stripes of the mucosal and muscularis propria layers , likely related to the presence of fat or edema in the submucosal layer . On fat-suppressed T2-weighted images it is possible to determine the nature of the bright signal as a persistent bright signal suggests the presence of edema , whereas complete suppression of the submucosal signal suggests fat infiltration and quiescent disease -LSB- 54 -RSB- . Extramural manifestations of disease that can be identified on MRI are fistulas , abscesses , fibrofatty proliferation , and enlarged lymph nodes . Diagnostic accuracy The accuracy of MRI of the small bowel has been extensively investigated . In many European institutions , conventional enteroclysis is increasingly being replaced by MRI enteroclysis or MRI enterography as MRI has proved to be highly accurate in both the detection of disease in patients with known IBD as in patients in whom IBD of the small bowel was suspected -LSB- 52 , 55 , 56 -RSB- . However , the studies that have been performed were mostly small and concerned selected populations with either a high suspicion of disease or known CD of the small bowel . Larger studies including the full spectrum of disease activity should be conducted . As was the case with CT and US , MRI is not suitable for the detection of superficial disease due to the limited spatial resolution . This finding is corroborated by a study comparing MRI and VCE in patients with CD -LSB- 57 -RSB- . Significantly more inflammatory lesions were detected with VCE in the jejunum and partly in the ileum of patients with CD . However , these findings had no effect on the therapeutic approach of the individual patients . The accuracy of MRI has not been compared with DBE as of yet . As mentioned before , MRI can be used for the evaluation of extramural disease . Due to the high contrast resolution abscesses are very conspicuous on T1-weighed fat suppressed images after the administration of intravenous Gadolinium . MRI is also very sensitive for the detection of fistulas -LSB- 47 , 52 , 58 -RSB- -LRB- Fig. 9 -RRB- . Fig. 9 . A 25-year-old female patient with known CD of the terminal ileum -LRB- same patient as pictured in Figs. 3 and 5 -RRB- . A Coronal T1-weighted image clearly shows the abscess -LRB- arrowheads -RRB- that was also depicted on US and CT. . B Coronal T1-weighted image showing a fistula In recent years , the accuracy of MRI for the detection of ileocolonic IBD has been investigated by means of MRI colonography . After administration of rectal contrast medium the colon -LRB- and sometimes the terminal ileum -RRB- was assessed for disease . Conflicting results were reported : while in one study high accuracy values were reported -LSB- 59 -RSB- , in others segmental sensitivity values were around 32 % -LSB- 60 , 61 -RSB- . Regarding the accuracy of MRI in differentiation between CD and UC conflicting results have been reported ; while some authors report that based on the location of inflammatory changes , the degree of involvement , the continuity or discontinuity of disease , and the presence of complications it was possible to differentiate between CD and UC -LSB- 51 , 62 -RSB- , others report a limited value in differentiation of disease -LSB- 63 -RSB- . Theoretically , a whole-bowel examination would be possible with MRI , by the administration of contrast medium orally and rectally . This has been attempted -LSB- 64 , 65 -RSB- and was deemed feasible . More research is needed to establish the diagnostic value of this combined approach . At the moment , MRI colonography does not seem to be able to replace CS . Discussion Compared with conventional imaging methods , CT , US , and MRI are accurate methods for the detection of IBD of the small bowel , both in patients suspected of disease as in patients with known IBD . Although subtle lesions can not be depicted with any of these modalities , clinically more relevant findings can be accurately depicted . Therefore , cross-sectional imaging should be incorporated in a comprehensive clinical evaluation of suspected IBD and for follow-up of CD . The exact role cross-sectional imaging techniques can play for follow-up in UC should be more extensively studied . As US is easily accessible , widely available , and inexpensive , it is recommended to use abdominal US as first-line modality in patients with suspected IBD of the small bowel . MR enterography would be a good alternative , especially as the assessment of the degree of disease activity can be better performed on MRI than on US . Although CT enterography is a very accurate technique and is used in many institutions , its role in IBD is limited by the ionizing radiation needed , especially due to the repetitive use for follow-up in often young individuals . If possible , it might be advisable to reserve this technique for patients in whom imaging is needed at very short notice as CT enterography can be performed very fast and is readily available . Although VCE has shown to be more accurate in depicting subtle lesions in the small bowel than MRI or CT , its role should be limited as of yet as the true benefit of VCE is not clear yet . As there are presently no standardized criteria for the diagnosis of CD with VCE , definitions with regard to what constitutes a positive finding might differ between studies . Moreover , the clinical significance of finding a single mucosal break or a few superficial aphthous lesions is not clear yet . Also , specificity and positive predictive values for VCE have not been established . At this time , it might be good to reserve VCE as a second-line modality if cross-sectional imaging has not shown abnormalities but the suspicion of disease remains standing despite these negative findings .

O O B I I O B I O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O B O B I I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

inflammatory bowel disease
ultrasonography
magnetic resonance imaging
computed tomography
diagnostic performance


Selected isotope ratio measurements of light metallic elements -LRB- Li , Mg , Ca , and Cu -RRB- by multiple collector ICP-MS The unique capabilities of multiple collector inductively coupled mass spectrometry -LRB- MC-ICP-MS -RRB- for high precision isotope ratio measurements in light elements as Li , Mg , Ca , and Cu are reviewed in this paper . These elements have been intensively studied at the Geological Survey of Israel -LRB- GSI -RRB- and other laboratories over the past few years , and the methods used to obtain high precision isotope analyses are discussed in detail . The scientific study of isotopic fractionation of these elements is significant for achieving a better understanding of geochemical and biochemical processes in nature and the environment . Introduction The development of multiple collector inductively coupled mass spectrometry -LRB- MC-ICP-MS -RRB- about 15 years ago immediately indicated the advantages of this technique , at least in ratio measurements from mass 80 and above . In general , the acquired data showed precision equal or better to the well-established thermal ionization mass spectrometry -LRB- TIMS -RRB- -LSB- 1 , 2 -RSB- . The ease of data acquisition was remarkable , the ionization efficiency was significantly larger , and consequently the sensitivity was improved . When MC-ICP-MS was introduced it had to compete with TIMS , which at that time was fully developed and provided the best isotope ratio data for metallic elements in terms of precision and accuracy . Even in the stages of application tests MC-ICP-MS exhibited several advantages : high precision , high reproducibility , high analytical throughput , simple sample preparation , and , as mentioned above , improved sensitivity -LSB- 3 -RSB- . MC-ICP-MS requires a more complicated instrument compared to TIMS . It uses an ion source at atmospheric pressure and therefore requires a specially designed ion beam introduction inlet system equipped with efficient pumping systems to reduce the argon gas pressure to 10 − 7 − 10 − 8 mbar . Further pumping systems along the ion flight tube maintain the vacuum at 2 × 10 − 9 mbar . The ion beam emerging from the interface has a circular profile which requires a tunable quadrupole lens , efficiently changing it to a rectangular shape . This rectangular ion beam possesses ions with an energy spread of up to 30 eV . An electrostatic energy filter is used to separate an almost monoenergetic ion beam acceptable for the magnetic sector mass separator . A further inherent problem in an ICP-MS is the relatively high instability of the plasma , observed as fluctuations and drifts of the ion beam . A single collector system , whether a Faraday cup or an electron multiplier , is too slow to follow this instability ; therefore an array of Faraday cups -LRB- and also a Daly electron multiplier -RRB- is mounted at the end of the instrument , allowing the simultaneous monitoring of two or more ion beam intensities . This technique had already been applied in the multiple collector TIMS instruments . Plasma 54 -LRB- P54 -RRB- , the first MC-ICP-MS instrument manufactured by VG Elemental in the UK -LSB- 1 -RSB- , contained an ion collector equipped with seven Faraday cups and an analog Daly detector . A unique feature of all double focusing instruments is the wide flat-topped ion peak shape , which is of primary importance for high precision data acquisition . Two further modifications were applied to this instrument : a wide-end flight tube to allow simultaneous measurement of ions with large mass differences , such as U -- Pb or 6Li -- 7Li , and the addition of an electrostatic energy filter before the Daly detector to enhance abundance sensitivity measurements . Isotope ratio measurements using laser ablation have also been demonstrated -LSB- 4 -RSB- . Several years later VG Elemental-Thermo Elemental introduced the Axiom , a smaller double focusing instrument of vertical configuration , providing high mass resolution capability . This mass spectrometer was aimed for high precision , fast analytical work -LSB- 5 -RSB- . Several other MC-ICP-MS instruments were manufactured by other companies applying different approaches for efficient reduction of ionic spectral interferences formed by argon and atmospheric gases , e.g. , thermalizing the ions produced by the plasma , introducing a detection system comprising a fixed array of Faraday cups and ion counters , and including an adjustable ion beam dispersion device . Micromass in the UK introduced the IsoProbe MC-ICP-MS where an off-axis hexapole collision cell is mounted in a jacket between the second interface cone and a beam focusing system -LSB- 5 -RSB- . The cell is flushed with a low pressure inert gas which reduces the ion energy to less than 1 eV . Also spectral interferences such as ArC + , ArN + , ArO + , ArCl + , and dimers produced in the atmospheric plasma , which interfere with 52Cr + , 54Fe + , 56Fe + , 75As + , and 80Se + , respectively , are removed by collision-induced cleavage of the Ar -- X bonds , allowing measurement isotope ratios at masses below 80 . The remainder of the instrument comprises a magnetic mass separator and a multiple collector detection system . Nu Instruments in the UK introduced the Nu Plasma MC-ICP-MS . This machine , as with the Plasma 54 , was developed by P.A. Freedman who maintained the same basic concepts , but introduced a different design for almost all the modules . Essentially it is a forward geometry -LRB- electrostatic sector followed by magnetic sector -RRB- , double focusing mass spectrometer with a C-shape configuration compared to the S-shape of the P54 . The ion beam profile conversion system is of different construction and the electrostatic energy filter and the magnetic separator were changed in shape and size . The profound advance in this design is the multiple collector detection system . The detection module comprises an array of 15 fixed detectors , 12 Faraday cups , and three electron multipliers , in front of which a zoom lens system deflects each separated ion beam into a chosen detector . Also , one of the multipliers is equipped with a filter for cutting off the tail from highly abundant isotopes . A later model from Nu Instruments , the Nu1700 , is a large geometry , high resolution MC-ICP-MS -LSB- 6 -RSB- that allows one to overcome most of the interferences . Finnigan MAT in Germany introduced the Neptune MC-ICP-MS , a double focusing C-shape instrument with a large magnet providing 16 % mass dispersion , movable collector array , and high resolution capability . Flat-topped peaks are achievable at R > 4,000 -LSB- 7 -RSB- . When discussing isotope ratio measurements utilizing plasma ionization , several further phenomena should be mentioned . Isotopic fractionation is of utmost importance . It is caused by repulsive forces in the intensive positive ion beam emerging from the plasma and supersonic ion expansion through the sample cone . Both effects yield radial repulsion of the lighter isotope from the beam center , i.e. , increasing the heavy mass over light mass ratio . The fractionation effect is inversely mass dependent from several per mils in uranium to more than 10 % in lithium . It is constant in time , since fresh sample solution is continuously aspirated into the ion source . This is in contrast to TIMS ionization , where a fixed sample is used , permanently changing in composition as the lighter isotope is preferentially vaporized . Fractionation may be corrected in one of three techniques : -LRB- 1 -RRB- internal and -LRB- 2 -RRB- external normalization , including double spike method ; and -LRB- 3 -RRB- `` standard-sample-standard bracketing '' ; consecutive measurements of the same ratio in a sample and standard . Further details will be given when describing the ratio measurements in the elements discussed in this review . ICP mass spectrometry is subject to other interferences originating from various sources . Spectral interferences are products of interactions between the carrier gas and atmospheric gases or the solvent molecules . As mentioned above they obscure the lower mass range . Sodium ions in the sample solution in the case of copper analysis may interfere as ArNa + at mass 63 . Further cases are molecular interferences such as oxides , nitrides , and hydrides of trace elements in the solution and isobaric ion interferences . These cases can be removed by using expensive high resolution MS. Other ways to reduce interferences include using of desolvation nebulizer and chromatographic separation of the analyte from the matrix prior to introduction into the MS. This separation is also necessary to prevent the additional effects of mass fractionation connected with the matrix effect . In the case of the heavy isotope ratio measurements , this fractionation is corrected by internal or external normalization , but in the case of standard-sample-standard bracketing , generally used for light masses correction , the analyte must be carefully and precisely separated from the matrix . As with the stable isotopes of the light elements , the isotopic composition of a sample is given in δ units -LRB- ‰ -RRB- relative to standard -LRB- I is isotope , x and y are mass numbers -RRB- . Generally , the isotope variations are derived from bracketing the measured sample ratio with the mean ratios of a standard measured before -LRB- std1 -RRB- and after the sample run -LRB- std2 -RRB- , and are presented as deviations in parts per 1,000 of the measured ratio from that of the standard -LRB- normalizing -RRB- ratio : Results and discussion Lithium Lithium isotopes are of significant importance in a number of fields , such as geochemistry -LSB- 8 -- 11 -RSB- , astrophysics -LSB- 12 -- 13 -RSB- , nuclear technology -LSB- 14 -RSB- , and biomedicine -LSB- 15 -RSB- . MC-ICP-MS opened new frontiers in Li isotope measurements by providing high precision data -LRB- < 0.3 ‰ , 2σ -RRB- . Lithium isotopes fractionate during hydrothermal processes , and significant variations may be observed in 7Li/6Li ratios in water derived from marine sedimentary rocks and from hydrothermal altered igneous rocks , thereby providing valuable information regarding regional ground-water flow paths . Lithium isotopes are a powerful tracer of recycling processes in the Earth . This is particularly the case for understanding the geochemical evolution of the Earth 's mantle , because -LRB- a -RRB- Li is a moderately incompatible constituent of minerals in peridotite , -LRB- b -RRB- Li isotope ratios show large variations in the terrestrial system , caused by low-temperature fractionation and mixing , -LRB- c -RRB- Li is a fluid-mobile element . Therefore , combined with existing geochemical information , its isotopes could be powerful geochemical tracers , especially for fluid-related -LRB- metasomatic -RRB- mantle processes . In recent years , almost all lithium isotope studies dealing with geological and related systems have applied the MC-ICP-MS measurement technique . Lithium isotope ratio measurements require careful separation of Li from the matrix in natural samples . For solid samples , digestion and ion exchange chromatography separation are used in general ; liquid samples are processed by chromatographic separation -LSB- 16 -- 21 -RSB- . Acid leaching -LSB- 22 , 23 -RSB- and direct resin techniques -LSB- 24 -RSB- are also applied . The most rapid method of separation was published by Hall et al. -LSB- 21 -RSB- for TIMS and modified at the Geological Survey of Israel for MC-ICP-MS . Any traces of Na , K , Mg , Sr , and Rb were detected using this modified method , so the samples were sufficiently pure for ratio measurements by Nu Plasma MC-ICP-MS . The values of the ratio in standard L-SVEC NBS -LRB- NIST , Li2CO3 -RRB- are -LSB- 25 -RSB- , and in seawater -LSB- 26 -RSB- . A typical analysis sequence consists of blank , standard , blank , sample 1 , blank , standard , blank , sample 2 , and so on . Lithium ratio measurements exhibit time-dependent drifts and random shifts . Tomascak et al. -LSB- 16 -RSB- reported a typical 7Li/6Li ratio drift for the L-SVEC standard from 12.7 to 12.3 during an 8-h period . Nishio and Nakai -LSB- 17 -RSB- rejected data when two successive measurements of the bracketing standard ratio shifted by more than 2 ‰ . These authors also reported a stability of -LRB- 2σ -RRB- for an in-house isotope standard measured over an 8-month period . It is good practice to carry out the sample and standard measurements under identical instrumental and solution conditions . The analyte concentrations in both solutions should be as close as possible and the impurity levels identical and as low as possible . It should be noted that sample purity in TIMS analysis relative to MC-ICP-MS is of major importance , since the large isotopic fractionation in Li is highly sensitive to impurities in the loaded sample , especially when Na and K are interfering elements -LSB- 21 -RSB- . It was reported that a Na/Li ratio greater than approximately 5 may cause unstable instrumental fractionation -LSB- 16 -RSB- . Moriguti and Nakamura -LSB- 27 -RSB- developed a four-step chromatographic separation for Li purification , allowing precise TIMS Li ratio analyses . Bouman et al. -LSB- 28 -RSB- studied a wide range of Li samples originating from islands in the Pacific , Atlantic , and Indian Oceans . Thirty six samples and three standard materials were analyzed . The precision of these measurement are 0.01 -- 0.5 -LRB- ‰ -RRB- , 0.6 -- 1.0 -LRB- ‰ -RRB- , and 1.2 -- 1.9 -LRB- ‰ -RRB- for 22 , ten , and four samples , respectively . The data for standard materials are presented in Table 1 , which also summarizes selected MC-ICP-MS Li isotope ratio measurements in geological samples . Table 1Li isotopic composition in standards and selected natural samples relative to NIST NBS L-SVEC -LRB- ‰ -RRB- Sampleδ7Li ± 2σReferenceJR-2 rock standard3 .840.18 -LSB- 24 -RSB- Magmatic arc lavas -LRB- Kurile -RRB- -LSB- 18 -RSB- 8322/3 Onekotan4 .2 < 1.0 K33 Keli-Mutu5.1 < 1.0 VB30 granite − 1.41.0 -LSB- 19 -RSB- MG20 granite0 .81.0 Inorganic calcite CM019 − 7.60.6 -LSB- 20 -RSB- Coral Acropora21 .00.4 Indian Ocean water33 .01.2 -LSB- 21 -RSB- Atlantic Ocean water32 .11.2 Foraminifera Orbulina universa28 .41.6 Inorganically grown carbonates -LSB- 23 -RSB- Aragonite -LRB- salinity 10 psu -RRB- − 10.90.8 Calcite -LRB- salinity 50 psu -RRB- − 1.90.8 Seawater29 .70.4 -LSB- 28 -RSB- BHVO-1 rock standard5 .01.5 Seawater 680 W30 .70.4 -LSB- 29 -RSB- Mediterranean Sea30 .590.26 -LSB- 30 -RSB- Red Sea30 .490.12 Dead Sea28 .780.11 Yarkon spring15 .140.21 SC -1 olivine3 .41.0 -LSB- 31 -RSB- Ia/211 clinopyroxene − 2.41.0 M 1 saprolite − 11.61 -LSB- 32 -RSB- 10 saprolite0 .21 SH 65 Ocean Island basalt7 .0 < 1 -LSB- 35 -RSB- KRS9806 xenolith , Japan − 7.70.83 -LSB- 36 -RSB- 9708 xenolith , Australia6 .00.83 Zagami meteorite4 .40.5 -LSB- 38 -RSB- 15495 lunar low-Ti mare basalt5.60.214-1 amphibolite0 .91 -LSB- 39 -RSB- 12-2 amphibolite − 14.21 Bryant et al. -LSB- 29 -RSB- studied Li isotope ratio measurements by MC-ICP-MS under `` cold plasma '' conditions . The results are characterized by fewer baseline interferences and improved reproducibility as compared with conventional hot plasma techniques . The 2σ precisions for 1,200-W , 800-W , and 680-W plasma energy are conservatively estimated as 1.1 ‰ , 0.7 ‰ , and 0.5 ‰ , respectively . The effects of analyte , acid , and matrix concentrations were discussed . Seitz et al. -LSB- 31 -RSB- determined the Li isotopic composition of coexisting olivine , clinopyroxene , and orthopyroxene from spinel - and garnet-bearing peridotite xenoliths . The degree of intramineral fractionation correlated negatively with equilibration temperature . The lithium isotopic composition of saprolites developed on a granite and diabase dike from South Carolina was measured to document their behavior during continental weathering . A general trend of decreasing δ7Li with increasing weathering intensity was observed -LSB- 32 , 33 -RSB- . A similar study was carried out by Kısakürek et al. -LSB- 34 -RSB- . The internal precision on 7Li/6Li measurements was usually less than 0.20 ‰ , and the external precision of Nu Plasma MC-ICP-MS , was 0.8 ‰ . Ryan et al. -LSB- 35 -RSB- defined lithium isotope variations in mantle sources -LRB- volcanic rocks from the Antarctica oceanic islands -RRB- , and Nishio et al. defined lithium isotope variations in mantle-derived xenoliths -LSB- 36 -RSB- . These isotopic measurements have provided much information on the mantle source region . Similarly , Elliott et al. -LSB- 37 -RSB- showed that Li isotopes promise to provide significant new constraints on the distribution of recycled material in the mantle and its implications for mantle convection . Lithium isotope compositions and concentrations of lunar samples , including basalts , breccias , and glass , and martian meteorites were measured using Thermo Finnigan MC-ICP-MS -LSB- 38 -RSB- . Teng et al. -LSB- 39 -RSB- measured lithium isotopic compositions in the country-rock amphibolites and schists using Nu Plasma MC-ICP-MS . δ7Li decreased dramatically with contact distance -LRB- along a − 10 m traverse from the pegmatite into amphibolite -RRB- from +7.6 to − 19.9 . Pogge von Strandmann et al. -LSB- 40 -RSB- investigated the behavior of Li isotopes in glaciated basaltic terrain . The δ7Li value of the suspended load was always lower than that of the bedload due to preferential retention of 6Li in secondary minerals during weathering . In turn , the δ7Li value of the dissolved load was always greater than that of the bedload . The authors suggested that δ7Li decreases with increasing chemical weathering . Similarly , Hathorne and James -LSB- 41 -RSB- used Li isotopes in seawater as a tracer for silicate weathering and showed that between 16 and approximately 8 Ma silicate weathering rate has increased , while weathering intensity has decreased . Nishio et al. -LSB- 42 -RSB- studied Li isotope ratios in North Atlantic and Indian Ocean waters and its relation to those of Sr and Nd . The Li isotope results support the recent proposal that significant amounts of recycled lower continental crust might produce the radiogenic isotope signatures of the Indian Ocean basalts . Rudnick and Ionov -LSB- 43 -RSB- examined Li isotopic disequilibrium in olivine and clinopyroxenes from far-east Russia . Jeffcoate et al. -LSB- 44 -RSB- studied Li isotope fractionation in peridotites and mafic melts . Their results highlight the potential of Li isotopes as a high resolution geospeedometer of the final phases of magmatic activity and cooling . Wunder et al. -LSB- 45 -RSB- studied Li isotope fractionation between Li-bearing staurolite , Li-mica , and aqueous fluids . Magnesium Magnesium has three naturally occurring isotopes at mass numbers 24 , 25 , and 26 with relative abundance of 78.99 , 10.00 , and 11.01 % , respectively . Galy et al. -LSB- 46 -RSB- briefly summarized the various fields where natural variations in the isotopic composition of this element may arise : -LRB- 1 -RRB- stellar nucleosynthesis and incorporation of presolar grains into meteorites , -LRB- 2 -RRB- the decay of 26Al to 26Mg , -LRB- 3 -RRB- isotopic fractionation in volatilization/condensation reactions , -LRB- 4 -RRB- isotopic fractionation during low temperature fluid/rock interactions , and -LRB- 5 -RRB- kinetic and thermodynamic isotope effects in biological processes . Galy et al. -LSB- 46 -RSB- performed high precision magnesium isotope ratio measurements using MC-ICP-MS for three groups of materials : commercial Mg materials including the NIST isotopic standard SRM 980 , natural magnesite , and commercial chlorophyll in spinach . The observed ratio 26Mg/24Mg was 0.139828 ± 0.000037 -LRB- 2σ -RRB- , compared to the NIST value of 0.13932 ± 0.000 6 -LRB- 2σ -RRB- -LSB- 47 -RSB- . The variations in the Mg materials reported in δ25Mg and δ26Mg units are given in Table 2 . A desolvation nebulizer was used to minimize the introduction of H2O , CO2 , O2 , and N2 , therefore reducing the presence in the plasma of molecular interferences such as , C2H + , , CN + , and NaH + . Other possible interferences are doubly charged ions such as 48Ca2 + , 48Ti2 + , 50Ti2 + , 50V2 + , 50Cr2 + , and 52Cr2 + . These elements , if present , should be removed by purification . Table 2Mg isotopic composition in standards and selected natural samples relative to DSM-3 -LRB- ‰ -RRB- Sampleδ26Mg ± 2σδ25Mg ± 2σReferenceAldrich Mg solution2 .600.171.330.08 -LSB- 46 -RSB- aDead Sea Mg metal3 .960.152.030.08 AG 177 magnesia2 .030.041.030.01 OUM 10988 magnesite , Italy1 .220.040.600.03 AG 27 chlorophill b , spinach1 .060.070.540.03 North Atlantic Sea water2 .590.041.330.08 -LSB- 51 -RSB- aMixed foraminifera − 1.880.16 − 0.990.10 Dolomite1 .640.040.880.01 Seawater -LSB- 52 -RSB- aEPR1 surface1 .950.140.980.06 WP45N 5800 m2.010.161.000.04Med-T1 surface2 .020.071.050.09 Hydrothermal 2,650 m − 1.010.16 − 0.510.06 River water MB160 .760.460.380.22 MB60 .090.220.040.11 PH60 .220.060.110.06 PH5 − 1.010.16 − 0.510.14 Ganges − 1.390.06 − 0.70.09 -LSB- 53 -RSB- Amazon − 1.030.07 − 0.530.04 Lena − 1.280.08 − 0.660.02 Seawater − 0.840.130.430.15 -LSB- 54 -RSB- MT 66 solute − 1.740.07 − 0.900.07 Ett113 bulk silicate rock − 0.420.03 − 0.210.02 M 201 biotite − 0.070.09 − 0.010.00 MO33 100 -- 110 soil0 .020.010.010.01 Ace78 travertine − 4.010.11 − 2.060.07 Dead Sea water − 0.600.08 − 0.330.10 -LSB- 55 -RSB- Seawater − 0.740.05 − 0.360.12 Sataf spring − 2.500.10 − 1.300.10 Carbonaceous chondrites -LSB- 56 -RSB- 144A , Al-Ti diopside0 .110.06 − 0.090.12144 A , Al-Ti diopside − 2.740.11 − 1.740.11 Olivines -LSB- 57 -RSB- DR9894 Australia − 1.430.2 − 0.660.13ZS56-2 Siberia − 1.050.2 − 0.540.13 aRelative to NIST isotopic standard SRM 980 Variations of the Mg isotope ratio in the metallic chips of the NIST SRM 980 magnesium isotopic standard were shown using five different MC-ICP-MS instruments of two types -LSB- 48 -RSB- . The chips were 1 -- 50 mg in size . The differences in δ25Mg and δ26Mg of the SRM 980 were up to 4.2 and 8.19 ‰ , respectively , while the long-term repeatability of the δ values was up to 0.09 and 0.16 ‰ respectively . Because of the heterogeneity of the NIST reference material , two homogeneous isotope standards , DSM-3 -LRB- Dead Sea magnesium -RRB- and Cambridge1 were prepared and characterized . The heterogeneity of Mg isotopes was also reported by Zhu et al. -LSB- 49 -RSB- . Carignan et al. -LSB- 50 -RSB- discussed the isotopic homogeneity of existing reference materials and suggested the acceptance of DMS-3 as a new Mg isotope reference standard material . Chang et al. -LSB- 51 -RSB- developed a Mg separation technique for low-Mg biogenic carbonates with yields close to 100 % . The technique was applied to the determination of Mg isotopes in three natural samples : seawater , foraminifera , and dolomite . De Villiers et al. -LSB- 52 -RSB- established the magnesium isotopic composition of seawater and evaluated its constancy as a function of depth and geographic location . The authors demonstrated that the magnesium isotopic composition of ancient oceans can be used to make important inferences about the relative contribution of different lithologies to the global continental weathering flux . Tipper et al. -LSB- 53 , 54 -RSB- analyzed river water , rock , travertine , and soil and demonstrated that both Ca and Mg isotope ratios are fractionated during weathering . The Mg isotope composition of the rivers is intermediate between limestone and silicate rock . Silicate soil has a δ26Mg of − 0.03 ‰ , heavier than that of silicate rock by 0.5 ‰ . This fractionation in the soil creates a complementary groundwater reservoir of light Mg . Seasonal variations in Mg isotope ratios in the dissolved load are small , but define an array which can be modeled as a mixture between a fractionated groundwater reservoir and surface runoff . Mg isotope fractionation during brine evolution in the Dead Sea is presently being studied using the MC-ICP-MS technique -LSB- 55 -RSB- . Samples from the solar system were used for 26Al − 26Mg dating , by measuring the variations in the Mg ratios using laser ablation combined with MC-ICP-MS -LSB- 56 -RSB- . Pearson et al. -LSB- 57 -RSB- investigated Mg isotopic variations in the lithospheric mantle by analyzing olivine in mantle-derived peridotite xenoliths and megacrysts using a laser-ablation microprobe and MC-ICP-MS . δ26Mg ranges from − 3.01 to +1.03 ‰ and δ25Mg from − 1.59 to +0.51 ‰ , relative to the magnesium isotopic standard DSM-3 , were found . The in situ measurement of Mg isotopes thus provides a powerful new method for investigating processes in the mantle . Calcium Calcium has six stable isotopes at mass numbers 40 , 42 , 43 , 44 , 46 , and 48 with relative abundance of 96.941 , 0.647 , 0.135 , 2.086 , 0.004 , and 0.187 % , respectively . Halicz et al. -LSB- 58 -RSB- studied in detail the MC-ICP-MS isotope ratio measurements of calcium . The more important points are discussed here . Under normal instrumental operation conditions it is not possible to use the isotope 40Ca because it is masked by the intense 40Ar + ion beam . Furthermore , the ion dispersion of Ca isotopes is too large to allow the 48Ca − 42Ca mass range to be accommodated on the multicollector array ; therefore only 42Ca , 43Ca , and 44Ca are monitored . Ar-scattered interferences were monitored at half masses for elevated background correction . Corrections of doubly charged Sr were made by measuring doubly charged 87Sr2 + . A desolvation nebulizer was used to reduce molecular interferences such as , , and . The results for the Ca ratios in the studied sample are given in δ units in Table 3 and were derived using the bracketing technique relative to the NIST SRM 915a Ca standard . Table 3Ca isotopic composition in standards and selected natural samples relative to NIST SRM 915a -LRB- ‰ -RRB- Sampleδ44Ca ± 2σReferenceCaCO3 Merck0 .610.28 -LSB- 58 -RSB- 2-8-E3 speleothem0 .250.32 Acropora coral0 .580.16 Shell from marine organism -LSB- 59 -RSB- USGS EN-10.53 a0 .07 CaCO3 JM 9912 − 0.630.07 CaCO3 JM 4064 − 6.620.08 Inorganic calcite -LSB- 61 -RSB- CM0400 .090.2 CM039 − 0.070.2 Growth solution0 .310.2 Foraminifera -LSB- 62 -RSB- OMEX-12b0.210 .10 WIND-10b0.280 .11 Mediterranean Sea water0 .980.14 Seawater1 .090.09 -LSB- 54 -RSB- MT 66 solute0 .540.06 Ett113 bulk silicate rock0 .310.05 MO33 0-10 soil0 .510.05 MO33 100-110 soil0 .540.13 Ace78 travertine0 .140.05 Carbonate fluorapatite -LSB- 63 -RSB- OG-50.260.11 D4/010 .420.08 S30/030 .230.0132 a/010 .520.1232 / 01s0 .130.03 D49/01 − 0.230.06 aRelative to IAPSO seawater Wieser et al. -LSB- 59 -RSB- developed a high precision Ca isotope ratio measurement technique for a Finnigan Neptune magnetic sector ICP-MS . Delta values including δ44Ca/43Ca , δ44Ca/42Ca , and δ48Ca/42Ca were measured with an external reproducibility better than 0.2 ‰ in seawater and biogenic and non-biogenic marine carbonates . Fietzke et al. -LSB- 60 -RSB- developed a new technique for direct measurements of 44Ca/40Ca ratios on an MC-ICP-MS using `` cool plasma '' . Reducing the plasma energy from the usually applied approximately 1,300 W to about 400 W significantly reduced the 40Ar + isobaric effect , allowing simultaneous and precise measurements of the two Ca isotopes . Repeated measurements of the 44Ca/40Ca ratios in various Ca standard materials were in good agreement with data reported in the literature . Marriott et al. -LSB- 61 -RSB- investigated temperature dependence of Ca isotopes in solution , inorganic calcite , and foraminifera and concluded that they are lighter than in the growth solution , and only weakly dependent on temperature . Sime et al. -LSB- 62 -RSB- also found negligible temperature dependence of calcium isotope fractionation in planktonic foraminifera . River water , rock , travertine , and soil were studied by Tipper et al. -LSB- 54 -RSB- who demonstrated that Ca , as well as Mg isotope ratios , are fractionated during weathering . Fractionation of Ca during continental weathering is of importance to the global cycle of Ca . The riverine input of Ca to the oceans is controlled not only by the composition of the primary continental crust , but also by the size and composition of the fractionated reservoir on the continents . The impact on the oceanic cycle of Ca depends on the relative residence times of dissolved Ca in the ocean and the storage time of fractionated Ca . Soudry et al. -LSB- 63 -RSB- explained fluctuations of Tethyan phosphogenesis through time , and whether or not they reflect long-term changes in ocean circulation or in continental weathering . A δ44Ca increase during the Late Cretaceous -- Eocene also reflects a decrease in weathering Ca2 + fluxes together with increased biological removal of isotopically light Ca2 + , fostered by increased continental flooding and concomitant carbonate -LRB- chalk -RRB- sedimentation on shelves . The overall concordant trends between the measured δ44Ca , the eustatic sea level curve , and the sizes of the flooded continental area throughout the Early Cretaceous -- Eocene , point to a linkage between the Ca isotopic composition of paleoseawater and long-term paleogeographic and oceanographic changes . Steuber and Buhl -LSB- 64 -RSB- analyzed the calcium isotope composition in modern and ancient marine carbonates . No significant temperature dependence of Ca isotope fractionation was found in Cretaceous shells . δ44Ca of Cretaceous seawater was 0.3 -- 0.4 ‰ lower than that of the modern ocean . Chu et al. -LSB- 65 -RSB- developed a procedure for the precise determination of Ca isotope ratios in natural and organic samples , such as bones , milk , and other biological materials . The data demonstrated that geological/environmental conditions do not cause large variability and it was suggested that diet is the major cause for variations in bones ; so Ca isotope ratios may serve as a paleodiet tracer . Skeletal carbonates from the Tethyan realm were analyzed by Farkaš et al. -LSB- 66 -RSB- . The observed late Mesozoic δ44Casw was simulated using a Ca isotope mass balance model , and the results indicated that the variation in δ44Casw can be explained by changes in oceanic input fluxes of Ca that were independent of the carbonate ion fluxes . Sime et al. -LSB- 67 -RSB- interpreted Ca isotope behavior in marine biogenic carbonates . The 18 million year record of planktonic foraminifera in the Atlantic averages and is a good match to Neogene Ca isotope record based on foraminifera , but is not similar to those in bulk carbonates . There are also publications on Ca using seawater as a standard for normalization in the bracketing method . Copper Copper isotope ratio measurements have been used to determine natural isotope variations in ore geology , geochronology , and archaeometry -LSB- 68 , 69 -RSB- . Three different types of ICP-MS instrument , a quadrupole , a single collector magnetic sector , and a multicollector magnetic sector instrument , were compared by Diemer et al. -LSB- 70 -RSB- . Although precision of results significantly differed , excellent agreement was observed between results obtained using all the instruments . The results for the Cu-isotopic composition are given in Table 4 . Table 4Cu isotopic composition in standards and selected natural samples relative to SRM NIST 976 -LRB- ‰ -RRB- Sampleδ65Cu ± 2σReferenceNative copper -LSB- 71 -RSB- aOUM15126 Michigan , USA0 .450.06 OUM00061 Yekaterinburg , Russia − 0.330.06 OUM15127 Cornwall , England0 .410.06 Minerals OUM23585 malachite , England − 0.260.06 OUM1616 azurite , USA1 .590.06 OUM25139 chalcopyrite , England0 .070.06 Acc . Ser . 25300 chalcopyrite , Canada0.400.06G-4 chalcopyrite , sulfide deposits − 0.440.06Ultra-pure Cu standards -LSB- 75 -RSB- JMC Cu Axiom0 .6190.058 JMC Cu IsoProbe0 .6410.019 IMP Cu IsoProbe0 .200.10 IMP Cu IsoProbe0 .2070.049 Copper sulfide precipitates -LSB- 78 -RSB- A-Cu - 0 Cu -LRB- I -RRB- S bulk0.700.06A-Cu - 0 Cu -LRB- I -RRB- S precipitated − 2.520.06A-Cu-48 Cu -LRB- I -RRB- S bulk0.620.06A-Cu-48 Cu -LRB- I -RRB- S precipitated − 2.320.06C-Cu-0 Cu -LRB- OH -RRB- 2 bulk − 0.260.06C-Cu-0 Cu -LRB- OH -RRB- 2 precipitated − 0.540.06 Chalcopyrite from the Grasberg deposit region -LSB- 73 -RSB- aF1-001 Grasberg skarn0.1070.031XC05-001 Ertsberg diorite0.6330.035ES-005 Ertsberg skarn0 .1930.054 XC22001 pyrite shell0.2180.023XC25-002 bornite-2.69 Dalum − 0.2690.031 Alexandrinka VHMS sulfides -LSB- 76 -RSB- SW-1 -LRB- a -RRB- chalcopyrite0 .184 < 0.07SW-1 -LRB- b -RRB- quartz0 .318 < 0.07HV-1 -LRB- a -RRB- sphalerite0 .330 < 0.07CA-1 pyrite0 .054 < 0.07CB-1 -LRB- b -RRB- covellite − 0.300 < 0.07CB-2 -LRB- a -RRB- silicate − 0.058 < 0.07 Supergene copper sulfides -LSB- 81 -RSB- Tt-1 , El Teniente bornite0.370.16Tt-6 , El Teniente chalcopyrite − 0.150.16El-1 , El Salvador chalcopyrite0.810.16M-1 , Mocha chalcopyrite − 0.060.16 aOriginal results were given in ɛ units -LRB- parts per 10,000 -RRB- and have been converted to δ units MC-ICP-MS ratio determinations of copper were comprehensively studied by Zhu et al. -LSB- 71 -RSB- . A sample purification procedure was described , noting that possible isotope fractionation must be avoided . Potential interferences in 65Cu/63Cu ratio measurements are -LRB- 23Na40Ar -RRB- + and at mass 63 and -LRB- 25Mg40Ar -RRB- + at mass 65 . It has been shown that for samples where Na/Cu and Mg/Cu ratios are below 10 − 4 and 10 − 3 , respectively , and under instrumental working conditions applied in this study , the abundances of the polyatomic ions relative to Na + and Mg + were approximately 10 − 4 , i.e. , isobaric interferences were negligible . Two Cu isotope measurement procedures were used : the standard-sample-standard bracketing technique where variations are calculated relative to Cu isotope standard -LRB- SRM NIST 976 -RRB- as in Eq . 2 , and the `` doping '' technique -LSB- 2 -RSB- where the sample is doped with Zn at a concentration Cu/Zn ratio close to 1 . Early results were given in `` ɛ '' units , but in the last papers `` δ '' is accepted . A constant value of the 68Zn/66Zn ratio was used as a normalization factor to correct the measured 65Cu/63Cu ratios . External precision -LRB- 2σ -RRB- better than 0.03 ‰ and 0.06 ‰ was achieved by applying the doping and bracketing techniques , respectively -LSB- 71 -RSB- . Borrok et al. -LSB- 72 -RSB- presented a new method for efficient separation of Cu , Fe , and Zn from the greater concentrations of matrix elements using a single anion-exchange column with hydrochloric acid media . The possibility of laser ablation combined with a MC-ICP-MS for Cu isotope ratio determinations was presented by Graham et al. -LSB- 73 -RSB- About 160 solid samples were analyzed with a 2σ uncertainty of approximately 0.04 ‰ . Jackson and Günter -LSB- 74 -RSB- examined the influence of various processes of laser ablation on fractionation of the Cu isotope ratio . The data suggest that the dominant source of isotopic fractionation at high laser fluence was the preferential volatilisation of 63Cu during incomplete vaporization and ionization in the ICP of particles greater than approximately 0.5 μm in diameter . Mason et al. -LSB- 5 , 75 -RSB- performed a detailed study on spectral interferences across the mass range 63Cu to 70Zn and the mass discrimination corrections using two different MC-ICP-MS instruments : the double focusing VG Axiom and the single focusing Micromass IsoProbe . It was observed that the ion types and their intensities depend on the different instrumental configuration . The importance of removing problematic matrix components prior to the Cu and Zn measurements was also emphasized . Based on their method Mason et al. -LSB- 76 -RSB- studied Zn and Cu isotopic variability in the Alexandrinka sulfide ore deposit from the Urals , Russia . A further study on mass discrimination correction shows the importance of matrix removal , particularly Fe and Ti , the dependence of mass discrimination on Cu/Zn ratio in the solution and that sample introduction system with a desolvating membrane causes variable behavior of the Cu standard , probably due to variations in Cu oxidation state in the solution -LSB- 77 -RSB- . Ehrlich et al. -LSB- 78 -RSB- studied copper isotope fractionation between aqueous Cu -LRB- II -RRB- and CuS , the latter being precipitated from CuSO4 solution with Na2S under anoxic conditions . Using Ni as a doping agent and the standard-sample-standard bracketing technique a 2σ error of 0.06 ‰ was achieved . The mean fractionation factor at 20 °C was derived : . Additional experiments over the temperature range 2 -- 40 °C showed an inverse dependence of the fractionation factor on temperature . Markl et al. -LSB- 79 -RSB- used copper isotopes as monitors of redox processes in hydrothermal mineralization . The authors concluded that copper isotope analyses can not be easily used as a reliable fingerprint for the source of copper in archaeology and geology because the variation caused by redox processes within a single deposit is usually much larger than between deposits . However , Asael et al. -LSB- 80 -RSB- showed that systematically large Cu isotope fractionation occurred during redox processes in sedimentary copper ore deposits . Cu isotope fractionation was also observed in bacterial oxidizing environments -LSB- 81 -RSB- . The roles of Cu and Zn isotopes in chondrites and iron meteorites were studied by Luck at al. -LSB- 82 , 83 -RSB- . A typical error -LRB- external precision -RRB- for δ65Cu ± 0.4 -- 0.5 ‰ was reported . Moynier et al. -LSB- 84 -RSB- investigated isotopic composition of zinc , copper , and iron in lunar samples . Recently isotopic ratio studies of Cu and Zn were performed in seawater -LSB- 85 -RSB- . The very low concentration of these elements and high TDS matrix demanded development of preconcentration and purification , followed by separation processes . In this work accurate data and their uncertainties are given only for Zn . Conclusions We have reviewed a group of more than 60 papers that were published in the period from 2000 up to present . We also quote results from a few unpublished works made at the GSI . We have chosen to focus on the isotope ratio determinations of only four elements , namely lithium , magnesium , calcium , and copper , where high precision ratio measurements were for various reasons impossible to achieve with the early MC-ICP-MS instruments . The second-generation machines have detection systems with sufficient dispersion to accommodate Li ions and the capability to be tuned to partial mass numbers . The high resolution capability allows one in some cases to resolve interferences . New types of desolvation nebulizers allow significant reduction of solvent and atmospheric interferences and the `` cold plasma '' technique reduces nebulizing gas ion intensities . Consequently , precision -LRB- ± 2σ -RRB- for δ7Li , δ25 , 26Mg , δ44Ca , and δ65Cu down to the range of -LRB- 0.1 -- 0.2 -RRB- ‰ , -LRB- 0.01 -- 0.1 -RRB- ‰ , -LRB- 0.05 -- 0.1 -RRB- ‰ and -LRB- 0.06 -- 0.15 -RRB- ‰ , respectively , can now be achieved .

O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O 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