Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

Continuous passive motion following total knee replacement: a prospective randomized trial with follow-up to 1 year

We have carried out a prospective randomised, single blind clinical trial to investigate the effect of continuous passive motion on range of knee flexion, lack of extension, pain levels and analgesic use after total knee replacement surgery. 85 subjects were randomly allocated to control or study group. All subjects followed the existing rehabilitation protocol, which permits immediate active range of motion exercises and mobilisation with the study group using continuous passive motion for 1 h, twice a day. Outcome measures employed were range of motion, pain assessed on a visual analogue scale and analgesic use according to the WHO ladder. Blinded evaluation was carried out preoperatively, at time of discharge from hospital, 6 weeks, 6 and 12 months postoperation. No significant difference was observed between groups at all time intervals for each outcome variable using Wilcoxon Rank sum tests. The results substantiate previous findings that short duration continuous passive motion following total knee arthroplasty does not influence outcome of range of motion or reported pain.     

Pharmacokinetics of the 13C labeled anticancer agent temozolomide detected in vivo by selective cross-polarization transfer

The anticancer agent temozolomide labeled with ¹³C (8-Carbamoyl-3-13C-methylimidazo-[5,1-d]-1,2,3,5-tetrazin-4-(3H)-one), was noninvasively detected in subcutaneous RIF-1 tumors by a selective cross polarization ¹³C NMR method, at a field strength of 9.4T. Pharmacokinetics of the drug, at a dose of 150 mg/kg, were determined for intravenous and intraperitoneal modes of administration (three animals per mode). The half-life of the drug in the tumors was approximately 60 min. The uptake and clearance of the drug, however, varied significantly between individual hosts, for both modes of administration. These results demonstrate the feasibility of obtaining pharmacokinetics of anticancer agents for individual tumors without the need for a label that might modify drug activity (e.g., fluorine). The variability of the in vivo measurements, even within the same tumor model, demonstrates the necessity of directly monitoring the tumor to evaluate drug pharmacokinetics.     

Relationship between TISS and ICU cost

Objective: To determine whether the therapeutic intervention scoring system (TISS) reliably reflects the cost of the overall intensive care unit (ICU) population, subgroups of that population and individual ICU patients. Design: Prospective analysis of individual patient costs and comparison with TISS. Setting: Adult, 12 bedded general medical and surgical ICU in a university teaching hospital. Subjects: Two hundred fifty-seven consecutive patients including 52 coronary care (CCU), 99 cardiac surgery (CS) and 106 general ICU (GIC) cases admitted to the ICU during a 12-week period in 1994. A total of 916 TISS-scored patient days were analysed Main outcome measures: A variable cost (VC) that included consumables and service usage (nursing, physiotherapy, radiology and pathology staff costs) for individual patients was measured daily. Nursing costs were calculated in proportion to a daily nursing dependency score. A fixed cost (FC) was calculated for each patient to include medical, technical and clerical salary costs, capital equipment depreciation, equipment and central hospital costs. The correlation between cost and TISS was analysed using regression analysis. Results: For the whole group (n = 257) the average daily FC was ￡ 255 and daily VC was ￡ 541 (SEM 10); range ￡ 23–￡ 2,806. In the patient subgroups average daily cost (FC + VC) for CCU was ￡ 476 (SEM 17.5), for CS ￡ 766 (SEM 13.8) and for GIC ￡ 873 (SEM 13.6). In the group as a whole, a strong correlation was demonstrated between VC and the TISS for each patient day (r = 0.87, p < 0.001) and this improved further when the total TISS score was compared with the total VC of the entire patient episode (r = 0.93, p < 0.001). This correlation was maintained in CCU, CS and GIC patient cohorts with only a small median difference between actual and predicted cost (2.2 % for GIC patients). However, in the individual patient, the range of error was up to ± 65 % of the true variable cost. For the whole group the variable cost per TISS point was ￡ 25. Conclusion: These results demonstrate that TISS reliably measures overall ICU population costs as well as those of the subgroups CCU, CS and GIC. However, the relationship between TISS and cost is less reliable for the individual patient. Received: 4 August 1997 Accepted: 22 March 1998     

Perforated duodenal ulcer and cigarette smoking.

Whilst the association between smoking and peptic ulceration has been reported previously, the relationship between smoking and the complications of ulcers, such as perforation, bleeding or acute painful exacerbation, has not been examined. In a retrospective study comparing 275 emergency admissions for peptic ulcer with 275 controls, cigarette smoking was significantly more common only in those with a perforated duodenal ulcer. Of 128 patients with perforated duodenal ulcers, 110 (86%) were cigarette smokers compared with 65 (51%) of the 128 matched controls (X2, P less than 0.01). Cigarette smoking in patients with bleeding or acutely exacerbated ulcers was not significantly more common than in controls. These findings strongly suggest a particular association between smoking and perforated duodenal ulcer.