Physiologically-based pharmacokinetic (PBPK) models provide a framework for in vitro-in vivo extrapolation of metabolic drug clearance. Many of the concepts in PBPK can have consequential impact on more mechanistic systems pharmacology models. In the gut wall, turnover of enzymes and enterocytes are typically lumped into one rate constant that describes the time dependent enzyme activity. This assumption may influence predictability of any sustained and dynamic effects such as mechanism-based inhibition (MBI), particularly when considering translation from healthy to gut disease. A novel multi-level systems PBPK model was developed. This model comprised a 'nested enzyme-within enterocyte' (NEWE) turnover model to describe levels of drug-metabolising enzymes. The ability of the model to predict gut metabolism following MBI and gut disease was investigated and compared to the conventional modelling approach. For MBI, the default NEWE model performed comparably to the conventional model. However, when drug-specific spatial crypt-villous absorption was considered, up to approximately 50% lower impact of MBI was simulated for substrates highly metabolised by cytochrome P450 (CYP) 3A4, interacting with potent inhibitors. Further, the model showed potential in predicting the disease effect of gastrointestinal mucositis and untreated coeliac disease when compared to indirect clinical pharmacokinetic parameters. Considering the added complexity of the NEWE model, it does not provide an attractive solution for improving upon MBI predictions in healthy individuals. However, nesting turnover may enable extrapolation to gut disease-drug interactions. The principle detailed herein may be useful for modelling drug interactions with cellular targets where turnover is significant enough to affect this process.

We aimed to determine how the hemodynamic parameters of the superior mesenteric artery are affected in mesenteric panniculitis.

Twenty-one patients with a diagnosis of mesenteric panniculitis on computed tomography were evaluated with duplex Doppler sonography. The control group consisted 20 asymptomatic volunteers. The peak systolic velocity, end-diastolic velocity (EDV), resistive index (RI), pulsatility index (PI), blood flow volume, and body mass index were measured in the group of patients with mesenteric panniculitis, and the findings were compared with those of the control group.

The mean blood flow volume and EDV were significantly higher in the patient group: The mean superior mesenteric artery blood flow volume ± SD was 917.86 ± 228.97 mL/min in the patient group versus 389.73 ± 92.72 mL/min in the control group (P < .001). The mean EDV was 31.56 ± 8.44 m/s in the patient group versus 19.27 ± 4.19 m/s in the control group (P < .001). The mean RI and PI were significantly lower in the patient group: The mean RI was 0.81 ± 0.04 in the patient group versus 0.85 ± 0.03 in the control group (P = .001). The mean PI was 2.69 ± 0.68 in the patient group versus 3.81 ± 1.13 in the control group (P = .001). the mean superior mesenteric artery diameter was 7.30 ± 0.67 mm in the patient group versus and 6.46 ± 0.66 mm in the control group (P < .001). The mean BMI was 27.95 ± 3.80 kg/m² in the patient group versus 23.16 ± 3.47 kg/m² in the control group (P < .001).

In patients with mesenteric panniculitis, the Doppler spectrum of the superior mesenteric artery shows detectable changes, which are characterized by decreased vascular resistance and increased blood flow.

Celiac disease (CD) is an autoimmune response to ingestion of gluten protein, which is found in wheat, rye, and barley grains, and results in both small intestinal manifestations, including villous atrophy, as well as systemic manifestations. The main treatment for the disease is a gluten-free diet (GFD), which typically results in the restoration of the small intestinal villi, and restoration of other affected organ systems, to their normal functioning. In an increasing number of recently published studies, there has been great interest in the occurrence of alterations in the cardiovascular system in untreated CD. Herein, published studies in which CD and cardiovascular terms appear in the title of the study were reviewed. The publications were categorized into one of several types: (1) articles (including cohort and case-control studies); (2) reviews and meta-analyses; (3) case studies (one to three patient reports); (4) letters; (5) editorials; and (6) abstracts (used when no full-length work had been published). The studies were subdivided as either heart or vascular studies, and were further characterized by the particular condition that was evident in conjunction with CD. Publication information was determined using the Google Scholar search tool. For each publication, its type and year of publication were tabulated. Salient information from each article was then compiled. It was determined that there has been a sharp increase in the number of CD - cardiovascular studies since 2000. Most of the publications are either of the type "article" or "case study". The largest number of documents published concerned CD in conjunction with cardiomyopathy (33 studies), and there have also been substantial numbers of studies published on CD and thrombosis (27), cardiovascular risk (17), atherosclerosis (13), stroke (12), arterial function (11), and ischemic heart disease (11). Based on the published research, it can be concluded that many types of cardiovascular issues can occur in untreated CD patients, but that most tend to resolve on a GFD, often in conjunction with the healing of small intestinal villous atrophy. However, in some cases the alterations are irreversible, underscoring the need for CD screening and treatment when cardiovascular issues arise of unknown etiology.

Celiac disease is an autoimmune disorder that causes inflammation and destruction in the small intestine of genetically susceptible individuals following ingestion of gluten. Awareness of the disease has increased; however, it remains a challenge to diagnose. This review summarizes the intestinal and extraintestinal cross-sectional imaging findings of celiac disease. Small intestine fold abnormalities are the most specific imaging findings for celiac disease, whereas most other imaging findings reflect a more generalized pattern seen with malabsorptive processes. Familiarity with the imaging pattern may allow the radiologist to suggest the diagnosis in patients with atypical presentations in whom it is not clinically suspected. Earlier detection allows earlier treatment initiation and may prevent significant morbidity and mortality that can occur with delayed diagnosis. Refractory celiac disease carries the greatest risk of mortality due to associated complications, including cavitating mesenteric lymph node syndrome, ulcerative jejunoileitis, enteropathy-associated T cell lymphoma, and adenocarcinoma, all of which are described and illustrated. Radiologic and endoscopic investigations are complimentary modalities in the setting of complicated celiac disease.

A consensus on the best imaging modality evaluating inflammatory bowel disease in the pediatric population is lacking and it is often unclear which modality to choose in specific clinical circumstances. Children with inflammatory bowel disease are exposed to ionizing radiation from multiple imaging studies performed at initial diagnosis, throughout treatment and during the follow-up period. This paper discusses the value of different imaging techniques in pediatric patients with inflammatory bowel disease and gives a review of the literature. In addition, particular features of inflammatory bowel disease in children including the predilection of affected segments in the gastrointestinal tract are highlighted. Based on current literature knowledge, we encourage an integrative approach to the interpretation of clinical and imaging data for diagnosis and follow-up in daily clinical settings.

Velocity measurement errors were investigated for an array-based preclinical ultrasound scanner (Vevo 2100, FUJIFILM VisualSonics, Toronto, ON, Canada). Using a small-size rotating phantom made from a tissue-mimicking material, errors in pulse-wave Doppler maximum velocity measurements were observed. The extent of these errors was dependent on the Doppler angle, gate length, gate depth, gate horizontal placement and phantom velocity. Errors were observed to be up to 172% at high beam-target angles. It was found that small gate lengths resulted in larger velocity errors than large gate lengths, a phenomenon that has not previously been reported (e.g., for a beam-target angle of 0°, the error was 27.8% with a 0.2-mm gate length and 5.4% with a 0.98-mm gate length). The error in the velocity measurement with sample volume depth changed depending on the operating frequency of the probe. Some edge effects were observed in the horizontal placement of the sample volume, indicating a change in the array aperture size. The error in the velocity measurements increased with increased phantom velocity, from 22% at 2.4 cm/s to 30% at 26.6 cm/s. To minimise the impact of these errors, an angle-dependent correction factor was derived based on a simple ray model of geometric spectral broadening. Use of this angle-dependent correction factor reduces the maximum velocity measurement errors to <25% in all instances, significantly improving the current estimation of maximum velocity from pulse-wave Doppler ultrasound.

Non-invasive measurement of splanchnic hemodynamics has been utilized in the clinical setting for diagnosis of gastro-intestinal disease, and for determining reserve blood flow (BF) distribution. However, previous studies that measured BF in a "single vessel with small size volume", such as the superior mesenteric and coeliac arteries, were concerned solely with the target organ in the gastrointestinal area, and therefore evaluation of alterations in these single arterial BFs under various states was sometimes limited to "small blood volumes", even though there was a relatively large change in flow. BF in the lower abdomen (BF(Ab)) is potentially a useful indicator of the influence of comprehensive BF redistribution in cardiovascular and hepato-gastrointestinal disease, in the postprandial period, and in relation to physical exercise. BF(Ab) can be determined theoretically using Doppler ultrasound by subtracting BF in the bilateral proximal femoral arteries (FAs) from BF in the upper abdominal aorta (Ao) above the coeliac trunk. Prior to acceptance of this method of determining a true BF(Ab) value, it is necessary to obtain validated normal physiological data that represent the hemodynamic relationship between the three arteries. In determining BF(Ab), relative reliability was acceptably high (range in intra-class correlation coefficient: 0.85-0.97) for three arterial hemodynamic parameters (blood velocity, vessel diameter, and BF) in three repeated measurements obtained over three different days. Bland-Altman analysis of the three repeated measurements revealed that day-to-day physiological variation (potentially including measurement error) was within the acceptable minimum range (95% of confidence interval), calculated as the difference in hemodynamics between two measurements. Mean BF (ml/min) was 2951 ± 767 in Ao, 316 ± 97 in left FA, 313 ± 83 in right FA, and 2323 ± 703 in BF(Ab), which is in agreement with a previous study that measured the sum of BF in the major part of the coeliac, mesenteric, and renal arteries. This review presents the methodological concept that underlies BF(Ab), and aspects of its day-to-day relative reliability in terms of the hemodynamics of the three target arteries, relationship with body surface area, respiratory effects, and potential clinical usefulness and application, in relation to data previously reported in original dedicated research.

The intestinal wall can be visualized using high resolution transabdominal ultrasound. The normal intestinal wall thickness in the terminal ileum, cecum, and right and left colon is <2mm when examined with graded compression. It is important to appreciate that a contracted intestinal segment can be misinterpreted as a thickened wall. Vascularisation can be mainly displayed in the second hyperechoic layer (submucosal layer) as well as vessels penetrating the muscularis propria. Imaging of the gastrointestinal wall is dependent on the experience of the examiner as well dependent on the equipment used. Acute or chronic inflammation of the intestinal wall is accompanied by increased perfusion of the mesentery, which can be displayed non-quantitatively with colour duplex. In contrast, ischemia is characterised by hypoperfusion of the mesenteric arteries and the bowel wall. The most promising sonographic approach in assessing splanchnic arteries and the bowel wall is combining the analysis of superior and inferior mesenteric inflow by pulsed Doppler scanning (systolic and diastolic velocities, resistance index) with the end-organ vascularity by colour Doppler imaging diminishing the influence of examination technique only displaying bowel wall vascularity. Colour Doppler imaging has been described as helpful in a variety of gastrointestinal disorders, particularly in patients with Crohn's disease, celiac disease, mesenteric artery stenosis and other ischemic gastrointestinal diseases, graft versus host disease and hemorrhagic segmental colitis.

The pulsed Doppler method theoretically enables human arterial blood flow (BF) to be determined in all of the abdominal-pelvic organs (BF(AP)) by subtracting the bilateral proximal femoral arterial BF from the upper abdominal aorta BF above the coeliac trunk. Evaluation of BF(AP) is a potentially useful indicator of exercise or food intake related flow distribution to organs; however, there is a lack of information regarding the physiological significance of BF(AP), and the measurements are yet to be validated. The aims of the present study are to examine the range in BF(AP) among subjects, monitor physiological day-to-day variability in BF(AP) over three different days and then determine whether mean BF(AP) (averaged over the three different measurement days) is related to body surface area (BSA). Forty healthy males (19-39 years) with a wide range of body weights (51-89 kg) were evaluated in a sitting position following a 12 h fast. The above-mentioned three conduit arteries were measured to determine BF(AP) using pulsed Doppler with spectral analysis. The mean BF(AP) was 2078 +/- 495 ml min(-1) (mean +/- SD) (range, 1153-3285 ml min(-1)), which is in agreement with a previous study that measured the sum of BF in the major part of the coeliac, mesenteric and renal arteries. The physiological day-to-day variability (mean coefficient of variation) was 14.5 +/- 10.0%. Significant (p < 0.05) positive linear relationships were observed between BF(AP) and BSA as well as body weight, which is in good agreement with the results of a previous study. The present data suggest that BF(AP) determined by three-conduit arterial hemodynamics may be a valid measurement that encompasses physiologic flow to multiple abdominal-pelvic organ systems.

Small intestinal ultrasonography with anechoic contrast agents (SICUS) has been shown to have a diagnostic accuracy on small bowel morphology similar to X-ray barium follow-through. Although extremely investigated by transabdominal ultrasonography, celiac disease, a common disorder of the small bowel, has been never studied by SICUS.

To asses SICUS characteristics of celiac disease patients.

SICUS was performed using PEG 4000 as contrast agent. Twenty-three patients with celiac disease at the first diagnosis were enrolled and 30 healthy volunteers, matched for sex and age, were selected as control group. Celiac disease diagnosis was based on anti-gluten, anti-endomysium, and anti-transglutaminase positivity as well as jejunal histology. The following seven echographic parameters were considered: liquid endoluminal content before contrast, loop diameter, Kerckring's folds, peristaltic waves, ileal jejunalization, mesenteric lymphoadenomegaly, and Doppler resistance index (RI) of mesenteric superior artery. Statistical analysis was performed by Student's t test for unpaired data; one-way analysis of variance was used to correlate echographic and histologic pictures.

Loop diameter, Kerckring's fold number, peristaltic waves, and Doppler RI appeared to be significantly different between celiac disease patients and controls. Additionally, liquid content, ileal jejunalization, and mesenteric lymphoadenomegaly were present only in the celiacs (52.1%, 47.7%, and 95.6%, respectively), but not in controls. Only Doppler RI values significantly correlated with the histologic degree of damage.

SICUS could be a reliable and noninvasive technique to confirm a diagnosis of celiac disease performed using conventional investigations. The possibility of investigating the whole small bowel and the safety of repeating examinations could be useful in the follow-up of celiac patients.

Coeliac disease is characterized by structural and functional changes in the small bowel which may also result in haemodynamic changes.

To establish whether splanchnic haemodynamics can be modified by a gluten-free diet.

Ten coeliac patients and 10 paired healthy subjects.

Echo-Doppler measurements were made of splanchnic vessels both fasting and after a standard meal before and after 9 months of a gluten-free diet.

In comparison to controls, coeliac patients had higher superior mesenteric artery blood velocity and flow, with lower resistance indexes and higher portal vein velocity and flow, particularly 3 h after a meal. Postprandial hyperaemia was reduced and delayed in time. Intrasplenic resistance indexes were also significantly lower both fasting and after a meal. After 9 months of a gluten-free diet, no significant differences were observed between coeliac patients and controls, both fasting and after a meal.

Splanchnic haemodynamics is significantly changed in coeliac patients, mainly after a meal. On treatment with a gluten-free diet, both fasting and postprandial haemodynamics became normal.

Recent data have shown that superior mesenteric artery (SMA) flow rates are significantly increased in active Crohn's disease, suggesting that SMA flow may be a useful, non-invasive index of disease activity. The aim of this prospective study was to evaluate the use of SMA Doppler sonography as an indicator of Crohn's disease activity and to compare with clinical evaluation and the Crohn's disease activity index (CDAI).

Patients with active Crohn's (n = 19), inactive Crohn's (n = 17) and control subjects (n = 17) were evaluated. Categorization of disease activity was based on a reference standard. CDAI scores were also calculated independently. The SMA flow parameters evaluated were resistive index, pulsatility index, end diastolic velocity, peak systolic velocity, time averaged maximum velocity, cross-sectional area and maximum flow volume.

Using a three-group ANOVA for each of peak systolic velocity (PSV) (P = 0.01), end-diastolic velocity (EDV) (P = 0.04), pulsatility index (PI) (P = 0.003), time-averaged maximum velocity (TAMV) (P = 0.05), and maximum flow volume (TAMV.CSA) (P = 0.01), there was a significant effect of group. Using post-hoc tests, only EDV (P = 0.01), TAMV (P = 0.02) and TAMV.CSA (P = 0.003) were significantly different between active and inactive Crohn's disease, though with considerable overlap of values for EDV and TAMV. The mean CDAI scores were significantly different between patients with active Crohn's (287) and inactive Crohn's (71) (P = 0.0001) and correlated well with the reference standard.

Only three of several parameters previously described as allowing Crohn's disease activity assessment actually did so in our study. However, for two of these parameters (EDV, TAMV), there was overlap between the measurements in the active and inactive groups, thus limiting the ability to discriminate disease activity in practice. The degree of overlap for maximum flow volume (TAMV.CSA) between active and inactive disease was considerably less and this parameter may be more discriminatory of disease activity. On the other hand, we found CDAI scores to be accurate in disease categorization. We agree that there appear to be hyperdynamic changes in active Crohn's disease but suggest that Doppler ultrasound assessment does not reliably assess disease activity in routine clinical practice.

To examine whether distinct ultrasonographic (US) signs exist in patients with adult celiac disease.

In a partly retrospective study, abdominal sonograms were obtained in 11 patients with adult celiac disease. Fifty matched control subjects also were examined. After the patients had fasted overnight, they were examined with 2-4-MHz abdominal and high-frequency 5-10-MHz linear-array US transducers.

The authors found several US pathologic signs in patients with untreated disease, including abnormal fluid-filled small intestine in all 11 patients, flaccid and moderately dilated small-bowel loops (2.5-3.5 cm) in eight, slight diffuse thickening of the small-bowel wall (3-5 mm) in seven, increased peristalsis of the small intestine in eight, enlarged mesenteric lymph nodes (anteroposterior diameter 5-10 mm) in nine, dilated caliber of the superior mesenteric artery or portal vein in seven, free fluid in the abdominal cavity in five, and increased echogenicity of the liver in six. None of these signs was present in the control group.

There are several US signs associated with adult celiac disease. None of the signs identified is specific, but a combination of signs is characteristic and indicates suspicion of this disease in a high percentage of cases. US could help to avoid diagnostic delay, especially in patients who have atypical clinical presentations.

The redistribution of blood flow (BF) in the abdominal viscera during right-legged knee extension-flexion exercise at very low intensity [peak heart rate (HR), 76 beats/min] was examined by using Doppler ultrasound. While sitting, subjects performed a right-legged knee extension-flexion exercise every 6 s for 20 min. BF was measured in the upper abdominal aorta (Ao), right common femoral artery (RCFA), and left common femoral artery (LCFA). Visceral BF (BFVis) was determined by the equation [BFAo - (BFRCFA + BFLCFA)]. A comparison with the change in BF (DeltaBF) preexercise showed a greater increase in DeltaBFRCFA than in DeltaBFAo during exercise. This resulted in a reduction of BFVis to 56% of its preexercise value or a decrease in flow by 1,147 +/- 293 (+/-SE) ml/min at the peak workload. Oxygen consumption correlated positively with DeltaBFAo, DeltaBFRCFA, and DeltaBFLCFA but inversely with DeltaBFVis during exercise and recovery. Furthermore, BFVis (% of preexercise value) correlated inversely with both an increase in HR (r = -0.89), and percent peak oxygen consumption (r = -0.99). This study demonstrated that, even during very-low-intensity exercise (HR <90 beats/min), there was a significant shift in BF from the viscera to the exercising muscles.

Knowledge of splanchinic hemodynamics in celiac disease is scarce. The hemodynamic parameters of the superior mesenteric artery were evaluated by duplex Doppler ultrasonography in children with celiac disease to show whether histomorphologic changes in small bowel mucosa led to any alteration in splanchinic blood flow.

The hemodynamic parameters of the superior mesenteric artery were evaluated by Doppler ultrasonography in 23 children with celiac disease. Ten patients were studied at the time of diagnosis. The remaining 13 children were studied after complete clinical and histologic recovery induced by gluten-free diet. Additionally, 9 patients out of 13 who were on a gluten-free diet for about 2 years were given gluten challenge, and superior mesenteric artery blood flow was measured after the challenge. The results were compared with those of healthy children.

Peak systolic velocity of the superior mesenteric artery was higher in untreated celiac patients than in healthy controls and treated celiac patients. Peak systolic velocity of the superior mesenteric artery in the treated group of children was close to that of control subjects, implying that successful treatment with gluten-free diet improves hemodynamic changes. The comparison of Doppler ultrasonographic measurements of the challenge group before and after the gluten challenge revealed that the peak systolic velocity, resistive index, and blood flow of the superior mesenteric artery were changed significantly.

The pathophysiologic events in small bowel mucosa during the active phase of celiac disease induce some hemodynamic changes that can be detected noninvasively by duplex Doppler ultrasonography.

This study was conducted to determine how the hemodynamic parameters of the superior mesenteric artery are affected in small bowel diseases.

One hundred thirty-seven patients whose clinical symptoms suggested an intestinal abnormality were evaluated with duplex Doppler sonography. The control group comprised 42 subjects recruited from the medical staff or from patients referred for renal sonography.

In 38 patients with diverse small bowel diseases, mean blood flow volume to the superior mesenteric artery territory (1.115+/-0.470 l/min) was significantly greater (p < 0.01) and the mean resistance index (0.82+/-0.06) was significantly lower (p < 0.05) than the mean values in the control group (0.692+/-0.250 l/min and 0.85+/-0.04, respectively). The mean peak systolic velocity and end-diastolic velocity in bowel disease patients were higher than the mean values in the control group.

Various intestinal abnormalities share common Doppler findings, eg, increase in blood flow volume, increase in both peak systolic and end-diastolic velocities, and decrease in resistance index. However, the absence of these findings does not exclude the possibility of small intestinal disease because of the overlap of the measurements in diseased and healthy subjects.

Current knowledge on splanchnic haemodynamics in coeliac disease is limited and incomplete.

To evaluate splanchnic arterial and venous blood flow in coeliac disease.

In 22 coeliac (13 untreated, nine treated) patients and in nine healthy subjects the following variables were assessed: vessel diameter and mean flow velocity in portal vein, splenic vein, superior mesenteric vein, and superior mesenteric artery. Peak systolic velocity, end diastolic velocity and pulsatility index were also determined in the superior mesenteric artery. Five patients of the untreated group were re-evaluated after nine months on a gluten free diet.

Significant differences in haemodynamic variables between the three groups were shown only in the superior mesenteric artery. An increase in both mean flow velocity and end diastolic velocity and a reduction in pulsatility index occurred in untreated patients compared with treated patients (p < 0.002; p < 0.04; p < 0.035) and with healthy controls (p < 0.001; p < 0.025; p < 0.0003). Similar results were obtained for the five patients evaluated before and after treatment (p < 0.03; p < 0.02; p < 0.03), in whom the mean flow velocity in the superior mesenteric vein also decreased after treatment (p < 0.05). No significant differences were noted between treated coeliac patients and healthy controls.

In untreated coeliac disease there is a hyperdynamic mesenteric circulation that decreases after treatment.