Automaticity was induced in isolated guinea pig and cat papillary muscles by application of depolarizing constant current pulses. Increasing extracellular potassium from 1 to 15 mM caused a shift of pacemaker-like activity to less negative diastolic potentials and a decrease in maximum phase 4 slope. Membrane resistance, estimated from the relation of applied current to maximum diastolic potential, decreased when extracellular potassium was increased. Voltage clamps of cat papillary muscle demonstrated that action potentials activate a time-dependent outward current which has a reversal potential of -79.1 mV (+/- 0.99 SE, n = 20) at an extracellular potassium concentration of 5 mM. The reversal potential of this current varies with extracellular K+ with a slope of 50-60 mV per 10-fold concentration change. The current is activated by voltage clamps or action potential plateaus in the range of -30 to +30 mV. It has a time constant of deactivation which increases from approximately 100 to over 400 msec as clamp potential is increased from -90 to -60 mV. It is proposed that this current is equivalent to Ix1 demonstrated in other cardiac tissues and is responsible, in combination with inward currents, for automaticity in ventricular fibers.

This first study to explore the influence of obesity on UC showed that high BMI had rather a favorable effect on the prognosis, whereas low BMI pointed to a more severe course of the disease.

BACKGROUND & AIMS:Early detection of neoplastic lesions is essential in patients with long-standing ulcerative colitis but the best technique of colonoscopy still is controversial. METHODS:We performed a prospective multicenter study in patients with long-standing ulcerative colitis. Two colonoscopies were performed in each patient within 3 weeks to 3 months. In white-light (WL) colonoscopy, stepwise random biopsy specimens (4 biopsy specimens every 10 cm), segmental random biopsies (2 biopsy specimens in 5 segments), and targeted biopsy specimens were taken. In NBI colonoscopy, segmental and targeted biopsy specimens were taken. The sequence of WL and NBI colonoscopy was randomized. RESULTS:In 36 of 159 patients enrolled (22.6%), 54 lesions with intraepithelial neoplasia (IN) were found (51 low-grade, 3 high-grade). In WL colonoscopy we found 11 IN in stepwise biopsy specimens, 4 in segmental biopsy specimens, and 15 in targeted biopsy specimens. In NBI colonoscopy 7 IN were detected in segmental biopsy specimens and 24 IN were detected in targeted biopsy specimens. Almost all IN were found with one technique alone (k value of WL vs NBI, -0.86; P < .001). Statistically equivalent numbers of IN were found in NBI colonoscopywith targeted and segmental biopsy specimens as in WL colonoscopy with targeted and stepwise biopsy specimens, but with fewer biopsy specimens (11.9 vs 38.6 biopsy specimens, respectively; P < .001), and less withdrawal time was necessary (23 vs 13 min, respectively; P < .001). CONCLUSIONS:Stepwise biopsy specimens are indispensable in WL colonoscopy. The combination of targeted and segmental biopsy specimens in the NBI technique is as sensitive as targeted together with stepwise biopsy specimens in WL colonoscopy, but requires fewer biopsy specimens and less time. The highest sensitivity should be reached by combining the WL and NBI techniques by switching between the modes.

SUMMARY1. The objective was to find out what kind of information regarding systemic blood pressure is transduced by baroreceptors in vivo and how this information is coded in the receptor discharge.2. Carotid sinus pressure, e.c.g., and receptor action potentials were recorded for fifty-two single fibre carotid sinus receptors found in twenty decerebrated unanaesthetized cats. 3. The inflation and gradual deflation of an intraaortic catheter tip balloon manipulated the blood pressure in the carotid sinus in a way as to define the full in vivo stimulus-response curve for each receptor.4. Correlation coefficients were computed between stimulus and response variables for several points on the response curve of each receptor and for every possible combination of stimulus and response variables defined.5. Stimulus variables were (a) systolic, (b) diastolic, (c) mean, (d) pulse pressures and (e) peak positive dP/dt. Response variables were (a) average discharge rate, (b) peak instantaneous frequency, and (c) average burst frequency.6. For every fibre in the sample only the correlations between systolic, diastolic and mean pressures vs. average discharge rate were consistently high and positive. All other correlations were numerically low and/or negative.7. It was concluded that in vivo baroreceptors signal mainly pressure level (systolic, diastolic or mean) as opposed to pulse pressure or dP/dt, and that the average discharge rate is their best index of information content.

SUMMARY BackgroundDifferent oral formulations of 'mesalazine (mesalamine)' may have different efficacy in distal ulcerative colitis.

Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of patients with adult T-cell leukemia/lymphoma (ATLL) due to human T-cell lymphotropic virus type-1 (HTLV-1) infection. We previously showed that ATLL cells constitutively express high levels of PTHrP via activation of promoters P2 and P3, resulting in HHM. In this study, we characterized a nuclear factor-jB (NF-jB) binding site in the P2 promoter of human PTHrP. Using electrophoretic mobility shift assays, we detected a specific complex in Taxexpressing human T cells composed of p50/c-Rel, and two distinct complexes in ATLL cells consisting of p50/p50 homodimers and a second unidentified protein(s). Chromatin immunoprecipitation assays confirmed in vivo binding of p50 and c-Rel on the PTHrP P2 promoter. Using transient co-transfection with NF-jB expression plasmids and PTHrP P2 luciferase reporter-plasmid, we showed that NF-jB p50/p50 alone and p50/ c-Rel or p50/Bcl-3 cooperatively upregulated the PTHrP P2 promoter. Furthermore, inhibition of NF-jB activity by Bay 11-7082 reduced PTHrP P2 promoter-initiated transcripts in HTLV-1-infected T cells. In summary, the data demonstrated that transcriptional regulation of PTHrP in ATLL cells can be controlled by NF-jB activation and also suggest a Taxindependent mechanism of activation of PTHrP in ATLL.

Background & Aims Carcinoma associated with perianal fistula in Crohn’s disease is a pending threat for patients. This study was aimed to improve understanding and facilitate development of diagnostic and therapeutic strategies. Methods A retrospective case-control study was conducted at four German hospitals. The analysis included forty patients with proven malignancy associated with perianal Crohn’s fistulas and forty randomly-selected controls with fistulizing perianal Crohn’s disease. Differences between groups were analysed and multivariate calculations performed to describe risk factors for oncological outcomes. Results Histology revealed adenocarcinoma in 33/40 patients and squamous cell carcinoma in 7/40 patients. Compared to fistula patients without carcinoma, patients with malignancies associated to fistula had a diagnosis of Crohn’s disease in younger age. Crohn’s disease lasted longer in patients with malignancy (25.8 ± 9.0 vs. 19.6 ± 10.4; p=0.006). Fistula related findings differed significantly between both groups. Signs for complicated and severe fistulation including complex anatomy and chronic activity occurred significantly more often in patients with malignancy associated to fistula. Significant multivariate hazard ratios for overall mortality and progression-free survival were shown for histologic type of cancer, metastatic disease and R1 resection. Overall survival (OS) was 45.1±28.6 months and the 5-year survival rate was 65%. Conclusions In patients with adenocarcinoma or squamous cell carcinoma associated with perianal fistula in Crohn’s disease, fistula characteristics determine risk for malignancy. Early diagnosis influences outcomes, while treatment of chronic fistula activity may be key to preventing malignancy. Expert multimodal therapy is paramount for successful treatment of perianal fistula-associated malignancies.

Background and Aims In active ulcerative colitis [UC] refractory to mesalazine, escalation to either steroids or immunosuppression is common practice. The efficacy and safety of alternative escalation therapy with a novel leukocyte apheresis device were studied. Methods This was a prospective, randomized, controlled multicentre pilot study comparing leukocyte apheresis with prednisolone in refractory UC (disease activity index [DAI] ≥ 4 and ≤8). Group A received weekly apheresis over five consecutive weeks. Group P received oral prednisolone 40 mg/day tapered to 0 mg at week 6. The primary end point was steroid-free clinical remission [DAI ≤ 2] at week 12. Clinical response was also analysed. Results Twenty-four patients were enrolled, 13 of whom were randomized into group A and 11 into group P. Clinical remission off steroids at week 12 was achieved in 3/12 patients [25.0%] with apheresis and 2/10 [20.0%] with prednisolone [p = 1.0]. The response rate after 12 weeks was 75.0% in group A and 50.0% in group P. Mean DAI scores improved in both treatment groups [p = 0.008]. C-reactive protein decreased from 6.0 ± 5.3 to 3.8 ± 3.7 mg/L at 12 weeks in group A and increased from 5.2 ± 6.0 to 6.3 ± 7.9 mg/mL in group P. Both treatments were well tolerated. No unexpected serious adverse events were seen in group A. In group P one symptomatic infection with Clostridium difficile occurred. Conclusions In patients with active UC refractory to mesalazine a novel leukocyte apheresis showed promising results. A comparison with prednisolone revealed similar therapeutic effectivity and excellent safety, providing the chance to escalate without systemic steroids.