Clinical course of ulcerative colitis in patients with and without primary sclerosing cholangitis

BACKGROUND AND AIM: We noticed in our practice that patients with ulcerative colitis (UC) who have developed primary sclerosing cholangitis (PSC) experience a milder course of colonic disease. Our objective in this study was to define whether or not there is any difference between UC activity and its course in patients with and without PSC. METHODS: Nineteen patients with UC and PSC (eight male, mean age 25 years) were enrolled. To every patient with UC and PSC, three patients with UC alone (total of 57 patients, 28 male, mean age 24 years) matched for age at onset, duration of the disease and extension of colonic disease were selected as the control group. We used number of hospitalizations due to activity of UC and number of short corticosteroid administrations in various years of follow-up as variables indicating course and severity of the colonic disease in this period. For comparing trends of UC activity between two groups, we used repeated measures two-way analysis of variances. RESULTS: Mean duration of follow up in case and control groups was 12.2 +/- 5.7 and 11.4 +/- 4.9 years, respectively. Two groups had no significant difference in use of sulfasalzine or aminosalicylates. Number of hospitalizations and courses of steroid therapy because of UC activity decreased significantly over time (P < 0.000) in both groups, and it was significantly higher in controls than in cases (P = 0.045 and 0.032, respectively). CONCLUSIONS: Development of PSC in patients with UC might have a positive effect on colonic disease. Further investigations to evaluate the basis of this improvement are warranted.     

Deletion of the 60-loop provides new insights into the substrate and inhibitor specificity of thrombin

Structural data have indicated that the 60-loop of thrombin with 8-9 insertion residues is responsible for the restricted substrate and inhibitor specificity of thrombin. However,previous deletion of 3-4 residues of this loop (des-PPW and des-YPPW) did not widen the specificity of thrombin, but further restricted it. The partial deletion of this loop also dramatically impaired the reactivity of thrombin with antithrombin (AT), protein C and fibrinogen, implicating a role for the productive interaction of the 60-loop with the target macromolecules. To further investigate the role of this loop, a mutant of thrombin was expressed in mammalian cells in which all 8 residues (Tyr-Pro-Pro-Trp-Asp-Lys-Asn-Phe) of the 60-loop were deleted (des-60-loop). In contrast to the partially deleted loop mutants, it was discovered that the des-60-loop mutant cleaved small synthetic substrates, clotted purified fibrinogen, and activated protein C with a near normal catalytic efficiency; however, its activity toward cofactors V and VIII was impaired approximately 2-4-fold. Direct binding and AT inhibition studies in the presence of heparin revealed that the affinity of heparin for interaction with exosite-2 of des-60-loop thrombin was impaired, though the reactivity of the mutant with AT and other plasma serpins was not impaired, but rather improved approximately 2-fold. These results suggest that the 60-loop plays a key role in regulating the specificity of thrombin by shielding the active-site pocket, but its productive interaction with the target molecules may not be as critical as has been speculated in previous reports.     

Alopecia areata in Darier disease and clinical findings in five affected family members

A 32-year-old man known to have keratosis follicularis presented with a new problem of alopecia areata involving his scalp. His Darier disease had been present for 24 years and was manifested by pruritic eruptions that were more severe in the summer months. Other family members, including his father, brother, and two sisters suffered from similar skin manifestations.     

Imaging of multiple sclerosis: Role in neurotherapeutics

Magnetic resonance imaging (MRI) plays an ever-expanding role in the evaluation of multiple sclerosis (MS). This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected clinically isolated syndromes. In addition, MRI is a key tool in providing primary therapeutic outcome measures for phase I/II trials and secondary outcome measures in phase III trials. The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called normal-appearing brain tissue). However, all current MRI methodology suffers from limited specificity for the underlying histopathology. Conventional MRI techniques, including lesion detection and measurement of atrophy from T1- or T2-weighted images, have been the mainstay for monitoring disease activity in clinical trials, in which the use of gadolinium with T1-weighted images adds additional sensitivity and specificity for areas of acute inflammation. Advanced imaging methods including magnetization transfer, fluid attenuated inversion recovery, diffusion, magnetic resonance spectroscopy, functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS and may provide methods to monitor therapies more sensitively in the future. However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on neurotherapeutics.     

Comparison of manual vs. automated multimodality (CT-MRI) image registration for brain tumors.

Computed tomgoraphy-magnetic resonance imaging (CT-MRI) registrations are routinely used for target-volume delineation of brain tumors. We clinically use 2 software packages based on manual operation and 1 automated package with 2 different algorithms: chamfer matching using bony structures, and mutual information using intensity patterns. In all registration algorithms, a minimum of 3 pairs of identical anatomical and preferably noncoplanar landmarks is used on each of the 2 image sets. In manual registration, the program registers these points and links the image sets using a 3-dimensional (3D) transformation. In automated registration, the 3 landmarks are used as an initial starting point and further processing is done to complete the registration. Using our registration packages, registration of CT and MRI was performed on 10 patients. We scored the results of each registration set based on the amount of time spent, the accuracy reported by the software, and a final evaluation. We evaluated each software program by measuring the residual error between "matched" points on the right and left globes and the posterior fossa for fused image slices. In general, manual registration showed higher misalignment between corresponding points compared to automated registration using intensity matching. This error had no directional dependence and was, most of the time, larger for a larger structure in both registration techniques. Automated algorithm based on intensity matching also gave the best results in terms of registration accuracy, irrespective of whether or not the initial landmarks were chosen carefully, when compared to that done using bone matching algorithm. Intensity-matching algorithm required the least amount of user-time and provided better accuracy.     

Protective effect of enalapril on vascular reactivity of the rat aorta

Cardiovascular complications are the major cause of morbidity and mortality in patients with diabetes mellitus (DM). Strategies that interrupt the renin-angiotensin system have been shown to reduce the ensuing threatening risk factors. The present study was carried out to investigate the effect of subchronic administration of enalapril on the aortic reactivity of streptozotocin (STZ)-diabetic rats. For this purpose, STZ-diabetic rats received enalapril (10 and 20 mg/kg ip) daily for 2 months. Contractile responses to phenylephrine (PE) and relaxation responses to acetylcholine (Ach) and isosorbide dinitrate (ISD) were obtained from aortic rings. Concentration-response curves from enalapril-treated diabetic (ED) rats to PE were attenuated as compared to vehicle-treated diabetics (VD), especially at a dose of 20 mg/kg for enalapril. In addition, endothelium-dependent relaxation responses induced by Ach was significantly higher in ED rats as compared to diabetic ones. The endothelium-independent relaxation responses for ISD were also found not to be significantly different among the groups. Therefore, subchronic treatment of diabetic rats with enalapril in a dose-dependent manner could prevent the functional changes in vascular reactivity in diabetic rats.