Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group

BACKGROUND: Despite widespread use of aminosalicylates as maintenance treatment for ulcerative colitis (UC), patients still report troublesome symptoms, often nocturnally. AIM: To compare the efficacy and safety of balsalazide (Colazide) with mesalazine (Asacol) in maintaining UC remission. METHODS: A randomized, double-blind comparison of balsalazide 3 g daily (1.04 g 5-ASA) and mesalazine 1.2 g daily for 12 months, in 99 (95 evaluable) patients in UC remission. RESULTS: Balsalazide patients experienced more asymptomatic nights (90% vs. 77%, P=0.0011) and days (58% vs. 50%, N.S.) during the first 3 months. Balsalazide patients experienced more symptom-free nights per week (6.4+/-1.7 vs. 4.7+/-2.8; P=0.0006) and fewer nights per week with blood on their stools or on the toilet paper, mucus with their stools or with sleep disturbance resulting from symptoms or lavatory visits (each P < 0.05). Fewer balsalazide patients relapsed within 3 months (10% vs. 28%; P=0.0354). Remission at 12 months was 58%, in both groups. Similar proportions of patients reported adverse events (61% balsalazide vs. 65% mesalazine). There were five serious adverse events (two balsalazide, three mesalazine) and four withdrawals due to unacceptable adverse events (three balsalazide, one mesalazine), of which one in each group was also a serious adverse event. CONCLUSIONS: Balsalazide 3 g/day and mesalazine 1.2 g/ day effectively maintain UC remission and are equally well tolerated over 12 months. At this dose balsalazide prevents more relapses during the first 3 months of treatment and controls nocturnal symptoms more effectively.     

Benzo[b]fluoranthene: tumorigenicity in strain A/J mouse lungs, DNA adducts and mutations in the Ki-ras oncogene

The polycyclic aromatic hydrocarbon benzo[b]fluoranthene (B[b]F) is a pervasive constituent of environmental combustion products. We sought to examine the lung tumorigenic activity of B[b]F in strain A/J mice, to study the relationship between formation and decay of B[b]F-DNA adducts and to examine mutations in the Ki-ras proto-oncogene in DNA from B[b]F-induced tumors. Mice were given i.p. injections of 0, 10, 50, 100 or 200 mg/kg body wt and lung adenomas were scored after 8 months. B[b]F induced significant numbers of mouse lung adenomas in a dose-related fashion, with the highest dose (200 mg/kg) yielding 6.95 adenomas/ mouse, with 100% of the mice exhibiting an adenoma. In mice given tricaprylin, the vehicle control, there were 0.60 adenomas/mouse, with 55% of the mice exhibiting an adenoma. Based on dose, B[b]F was less active than benzo[a]pyrene. DNA adducts were analyzed qualitatively and quantitatively by 32P-post-labeling in lungs of strain A/J mice 1, 3, 5, 7, 14 and 21 days after i.p. injection. Maximal levels of adduction occurred 5 days after treatment with the 200 mg/kg dose group, producing 1230 amol B[b]F-DNA adducts/microgram DNA. The major B[b]F-DNA adduct was identified by co-chromatography as trans-9, 10-dihydroxy-anti-11, 12-epoxy-5-hydroxy-9, 10, 11, 12-tetra-hydro-B[b]F-deoxyguanosine. Approximately 86% of the tumors had a mutation in codon 12 of the Ki-ras oncogene, as determined by direct DNA sequencing of PCR-amplified exon 1 and single-stranded conformation polymorphism analysis. Analysis of the Ki-ras mutation spectrum in 25 of 29 B[b]F-induced tumors revealed the predominant mutation to be a G-->T transversion in the first or second base of codon 12, congruous with the DNA adduct data. Our data are consistent with previous reports in mouse skin implicating a phenolic diol epoxide as the proximate carcinogenic form of B[b]F that binds to guanine.     

Intussusception. Issues and controversies related to diagnosis and reduction

Co-operative oxygen binding by the vertebrate haemoglobins arises from an equilibrium between a quaternary structure with low affinity (T), favoured in the absence of ligand, and a high affinity form (R) adopted by the fully ligated protein. While R state haemoglobin has an oxygen affinity close to that of isolated subunits, the affinity of the T state is roughly 300-fold lower. The mechanism by which the T state restrains ligand binding, and the pathway of the quaternary transition, have been largely revealed by detailed crystallographic analyses of a number of haemoglobin molecules in the equilibrium states, as well as intermediate forms of the T state including partially ligated species. The ligation intermediates of the R state, however, have not been as well characterized structurally. We report here the crystal structure of one such intermediate species, namely, horse deoxyhaemoglobin in the R state, at 1.8 A resolution. While ligand binding in the T state may result in unfavourable stereochemistry in and around the haem-ligand complex, the more plastic R structure appears to accommodate equally well both liganded and ligand-free haem. Loss of ligand at the R state haem results in movements of the haem and shifts of the FG corners, which form characteristic intersubunit contacts that distinguish the quaternary states. The shifts are comparable in magnitude to the corresponding movements associated with de-ligation in the T state, although they differ in direction. These and other differences illustrate how the structural changes in the haem pocket are communicated to the subunit interfaces and how the movements that can occur in the R state may be impeded in the T state.     

The WHO multicenter study on Listeria monocytogenes subtyping: random amplification of polymorphic DNA (RAPD)

As part of a WHO multicenter study on Listeria monocytogenes subtyping methods the random amplification of polymorphic DNA (RAPD)-technique was evaluated. Six participants were asked to use a standard protocol to analyse a set of 80 L. monocytogenes strains. This set contained 22 groups of epidemiologically linked isolates and 11 pairs of duplicate strains. Using three different 10-mer primers the median reproducibility of the RAPD-results obtained by the six participants was 86.5% (range 0-100%). Failure in reproducibility was mainly due to results obtained with one particular primer. The number of epidemiological groups found to be homogeneous varied from 1-22 (median 16). However, for some groups an inhomogeneity was found by the majority of participants. The overall correlation between the results from the different participants ranged from 32 to 85%.     

Neuropsychological and motor functioning after unilateral anatomically guided posterior ventral pallidotomy. Preoperative performance and three-month follow-up

This study presents baseline and 3-month follow-up motor and neuropsychological data for 22 patients with Parkinson's disease (PD) who underwent anatomically guided unilateral posterior ventral pallidotomy (PVP). Postsurgical improvements were seen in psychomotor speed, fine motor accuracy, and dyskinesia, whereas grip strength decreased on the side contralateral to the surgery. No change was detected in overall level of cognitive functioning, nor were changes demonstrated in memory, language, or working memory when the entire sample of patients was evaluated. When the group was divided on the basis of side of surgery, patients with left-sided pallidotomies showed a decline in verbal fluency. Patients and caregivers reported improvement in psychosocial functioning. These initial findings of improved motor performance and largely unaffected cognitive functions are consistent with results obtained with functional PVP and provide support for the use of anatomically guided posterior ventral pallidotomy in the treatment of motor symptoms of PD.     

The proximal ligand variant His93Tyr of horse heart myoglobin

The spectroscopic and structural properties of the His93Tyr variant of horse heart myoglobin have been studied to assess the effects of replacing the proximal His residue of this protein with a tyrosyl residue as occurs in catalases from various sources. The variant in the ferric form exhibits electronic spectra that are independent of pH between pH 7 and 10, and it exhibits changes in absorption maxima and intensity that are consistent with a five-coordinate heme iron center at the active site. The EPR spectrum of the variant is that of a high-spin, rhombic system similar to that reported for bovine liver catalase. The 1D 1H-NMR spectrum of the variant confirms the five-coordinate nature of the heme iron center and exhibits a broad resonance at 112.5 ppm that is attributable to the meta protons of the phenolate ligand. This result indicates that the new Tyr ligand flips at a significant rate in this protein. The thermal stability of the Fe(III) derivative is unchanged from that of the wild-type protein (pH 8) while the midpoint reduction potential [-208 mV vs SHE (pH 8.0, 25 degrees C)] is about 250 mV lower. The three-dimensional structure of the variant determined by X-ray diffraction analysis confirms the five-coordinate nature of the heme iron center and establishes that the introduction of a proximal Tyr ligand is accommodated by a shift of the F helix (residues 88-99) in which this residue resides away from the heme pocket. Additional effects of this change are small shifts in the positions of Leu29, a heme propionate, and a heme vinyl group that are accompanied by altered hydrogen bonding interactions with the heme prosthetic group.(ABSTRACT TRUNCATED AT 250 WORDS)