The median time on GFD treatment was similar in both groups. Two patients were excluded after the safety phase because of a histological deterioration of two and three Marsh grades, respectively, which for one patient returned to normal (Marsh 0) after four weeks of exclusion. The patient that did not return to normal started the study with high IgA/G-DGP-tTG values. However, Dorsomorphin buy other CD-related antibodies remained undetectable in these two patients. The remaining 14 patients entered and completed the efficacy phase. Table 1 Demographic and baseline characteristics of the safety and efficacy phase When correlating the patients�� baseline characteristics with their response to gluten, highly significant inverse relationships were found between the patients�� time since diagnosis or time spent on a GFD and their response to gluten as measured by IgG-AG, IgA-tTG and IgA/G-DGP-tTG, and Marsh scores (data not shown).

Adverse events No serious adverse events occurred during the trial, patients reported no severe adverse events, and no patients withdrew during the trial. Complaints that were reported during the safety and efficacy phase were of gastrointestinal nature and mostly mild and transient. The number of reported gastrointestinal complaints did not differ between the AN-PEP and placebo group (Table (Table11). Celiac-disease quality of life The mean total scores of the four categories on the CD quality of life were relatively high (145-156 out of a total score of 196) in the total group and throughout both study phases. In the safety phase, the total CD quality of life score significantly (P = 0.

04) increased by 6 points during gluten with AN-PEP treatment. This increase was however lower than the 12-point increase that is considered a clinically relevant quality of life improvement[14]. In the efficacy phase, the individual or total CD quality of life scores of patients consuming gluten with placebo or gluten with AN-PEP did not significantly deteriorate. No differences between the groups were observed. The mean score for the gastrointestinal CD quality of life was relatively high throughout the study, indicating that gluten with AN-PEP was well tolerated. Mucosal biopsy immunohistology In the patients receiving gluten plus AN-PEP treatment in the safety phase, several patients showed variation in Marsh scores but overall no significant change in degree of mucosal damage, as indicated by changes in the Marsh score, Carfilzomib was observed (Table (Table2).2). Two of 16 patients were excluded from entering the efficacy phase as their mucosa showed an increase of two Marsh steps while 14 patients were considered histologically stable on gluten with AN-PEP.

For this reason, only changes in blood flow that persist for some time can be recorded. In the present experiments (study 1), the transverse colon was instrumented with a needle-type platinum EPZ-5676 clinical trial electrode, while a reference electrode was placed in the peritoneal cavity. As has been reported for the stomach (Holzer et al., 1991), the platinum electrode was inserted from the serosa tangentially to the colon at an angle of about 30 degrees and positioned in the submucosa of the colon. The reproducibility of placing the needle electrode in the submucosal layer of the colonic wall was confirmed by histology. To this end, the needle electrode was stained with blue ink before being placed in the colonic wall. After removal of the electrode, the tissue was rapidly excised and frozen.

Sections (35 ��m thick) of the tissue perpendicular to the needle track were taken in a cryostat and examined under a microscope. The needle track was invariably localised to the submucosal layer of the colonic wall, as observed in three rats. The measurement of CBF via the clearance of inhaled hydrogen gas was discontinuous, as the experimental protocol involved alternating 15 min periods of saturation, and desaturation, of the tissue with hydrogen gas (Holzer et al., 1991; Heinemann et al., 1999). The current representing the actual hydrogen concentration at the site of the electrode was taken up by a polarographic unit, amplified, digitised at a frequency of 1 Hz and recorded on a personal computer with a custom-made software (Heinemann et al., 1999).

The washout curve was then fitted to a monoexponential curve, the power of which was used to calculate the average CBF during the 15 min period of desaturation (Livingston et al., 1989). Average values of MAP and HR were determined for the same time periods. In addition, the colonic vascular conductance (CVC) value was calculated as CBF divided by MAP. Measurement of CBF with laser Doppler flowmetry The principle of laser Doppler flowmetry is based on the reflectance of monochromatic light by moving particles in the tissue. As the volume of tissue that is sampled is not precisely known, the technique cannot record blood flow in absolute values but in arbitrary perfusion units (PUs). The uncertainty about the tissue volume sampled also makes it difficult to compare recordings taken from different animals with each other because the vascular geometry of the tissue sample (i.

e. the relative proportion of arteries, arterioles and capillaries) may differ substantially but cannot be controlled adequately. The major advantages of the Carfilzomib technique are that it provides continuous recordings of blood flow and that it is able to detect rapidly occurring and short-lasting changes in this variable following an intervention. In all studies, except study 1, CBF was measured by laser Doppler flowmetry.