Development of a prognostic MRCP-score (DiStrict) for individuals with large-duct primary sclerosing cholangitis.

Background & Aims: Magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis and follow-up of individuals with primary sclerosing cholangitis (PSC). The aim of our study is to develop an MRCP-score based on cholangiographic findings previously associated with outcomes and assess its reproducibility and prognostic value in PSC. Methods: The score (DiStrict score) was developed based on the extent and severity of cholangiographic changes of intrahepatic and extrahepatic bile ducts (range 0-8) on 3D-MRCP. In this retrospective, multicentre study, three pairs of radiologists with different levels of expertise from three tertiary centres applied the score independently. MRCP examinations of 220 consecutive individuals with PSC from a prospectively collected PSC-cohort, with median follow-up of 7.4 years, were reviewed. Inter-reader and intrareader agreements were assessed via intraclass correlation coefficient (ICC). After consensus, the prognostic value of the score was assessed using Cox-regression and outcome-free survival rates were assessed via Kaplan-Meier estimates. Harrell's C-statistic was calculated. Results: Forty patients developed outcomes (liver transplantation or liver-related death). Inter-reader agreement between experienced radiologists was good (ICC 0.82; 95% CI 0.74-0.87, and ICC 0.81; 95% CI 0.70-0.87, respectively) and better than the agreement for the pair of experienced/less-experienced radiologists (ICC 0.48; 95% CI 0.05-0.72). Agreement between radiologists from the three centres was good (ICC 0.76; 95% CI 0.57-0.89). Intrareader agreement was good to excellent (ICC 0.85-0.93). Harrell's C was 0.78. Patients with a DiStrict score of 5-8 had 8.2-fold higher risk (hazard ratio 8.2; 95% CI 2.97-22.65) of developing outcomes, and significantly worse survival (p <0.001), compared to those with a DiStrict score of 1-4. Conclusions: The novel DiStrict score is reproducible and strongly associated with outcomes, indicating its prognostic value for individuals with PSC in clinical practice. Impact and implications: The diagnosis of primary sclerosing cholangitis (PSC) is based on magnetic resonance cholangiopancreatography (MRCP). However, the role of MRCP in the prognostication of PSC is still unclear. We developed a novel, simple, and reproducible risk-score, based on MRCP findings, that showed a strong association with prognosis in individuals with PSC (DiStrict score). This score can be easily used in clinical practice and thus has the potential to be useful in clinical trials and in patient counselling and management.

Methylphenidate and Reduced Overweight in Children With ADHD.

Objective: The objective of this study was to investigate odds ratios of overweight/obesity in children with ADHD and to compare the change in body mass index (BMI) after initiation of methylphenidate treatment in normal versus overweight/obese children. Method: This population-based study included 724 children (<18 years), of whom 197 were girls. Odds ratios for overweight and obesity were calculated, comparing the study group with a reference group from the same area. After initiation of methylphenidate treatment, changes in BMI were assessed for up to 3 years. Results: Children with ADHD had an odds ratio of 1.87 (95% confidence interval [CI]: [1.60, 2.19]) for overweight/obesity. A decrease in BMI standard deviation score was identified 1 to 3 years into treatment. The decrease was beneficially greater in overweight/obese as compared with normal weight children-mean (SD) -0.64 (0.80) versus -0.39 (0.68); p = .001-and greater in girls. Conclusion: Medication with methylphenidate may facilitate favorable weight development in children with ADHD and overweight/obesity.

Structural studies of ß-carbonic anhydrase from the green alga Coccomyxa: inhibitor complexes with anions and acetazolamide.

The ß-class carbonic anhydrases (ß-CAs) are widely distributed among lower eukaryotes, prokaryotes, archaea, and plants. Like all CAs, the ß-enzymes catalyze an important physiological reaction, namely the interconversion between carbon dioxide and bicarbonate. In plants the enzyme plays an important role in carbon fixation and metabolism. To further explore the structure-function relationship of ß-CA, we have determined the crystal structures of the photoautotroph unicellular green alga Coccomyxa ß-CA in complex with five different inhibitors: acetazolamide, thiocyanate, azide, iodide, and phosphate ions. The tetrameric Coccomyxa ß-CA structure is similar to other ß-CAs but it has a 15 amino acid extension in the C-terminal end, which stabilizes the tetramer by strengthening the interface. Four of the five inhibitors bind in a manner similar to what is found in complexes with α-type CAs. Iodide ions, however, make contact to the zinc ion via a zinc-bound water molecule or hydroxide ion--a type of binding mode not previously observed in any CA. Binding of inhibitors to Coccomyxa ß-CA is mediated by side-chain movements of the conserved residue Tyr-88, extending the width of the active site cavity with 1.5-1.8 Å. Structural analysis and comparisons with other α- and ß-class members suggest a catalytic mechanism in which the movements of Tyr-88 are important for the CO(2)-HCO(3)(-) interconversion, whereas a structurally conserved water molecule that bridges residues Tyr-88 and Gln-38, seems important for proton transfer, linking water molecules from the zinc-bound water to His-92 and buffer molecules.