Delayed O-methylation of l-DOPA in MB-COMT-deficient mice after oral administration of l-DOPA and carbidopa

1.?Catechol-O-methyltransferase (COMT) is involved in the O-methylation of l-DOPA, dopamine, and other catechols. The enzyme is expressed in two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-COMT), which is anchored to intracellular membranes.

2.?To obtain specific information on the functions of COMT isoforms, we studied how a complete MB-COMT deficiency affects the total COMT activity in the body, peripheral l-DOPA levels, and metabolism after l-DOPA (10?mg kg^?1) plus carbidopa (30?mg kg^?1) administration by gastric tube in wild-type (WT) and MB-COMT-deficient mice. l-DOPA and 3-O-methyl-l-DOPA (3-OMD) levels were assayed in plasma, duodenum, and liver.

3.?We showed that the selective lack of MB-COMT did not alter the total COMT activity, COMT enzyme kinetics, l-DOPA levels, or the total O-methylation of l-DOPA but delayed production of 3-OMD in plasma and peripheral tissues.     

Statins do not Increase the Rate of Bleeding Among Warfarin Users

Clinical significance of potential interaction between warfarin and statins is unclear. Our objective was to determine whether use of statins as a class or use of simvastatin modulates the rate of bleeding requiring hospitalization among new warfarin users. Using Finnish healthcare databases, we identified a cohort of 101,588 warfarin initiators between 1 January 2009 and 30 June 2012. By the end of 2012, these patients accumulated 92,695 person‐years of exposure to warfarin‐only and 60,253 years of exposure to warfarin‐with‐statin. The outcome was a composite of gastrointestinal, intracranial or other bleeding leading to hospitalization. A Poisson generalized estimating equation model was employed to estimate rate ratios (RR) and their 95% confidence intervals (CI) for exposure to warfarin‐with‐statin compared to warfarin‐only and to allow multiple episodes per patient and time‐dependent covariates. In multivariable models, we found no difference in the bleeding rate in association with exposure to any statin (multivariable‐adjusted RR = 0.98, 95% CI 0.89–1.07) or to simvastatin (RR = 1.01, 95% CI 0.91–1.11) with warfarin compared to exposure to warfarin‐only. We conclude that concomitant use of statins and warfarin was not associated with an increased rate of bleeding requiring hospitalization.     

Outcome of Patients with Esophageal Perforations: A Multicenter Study

Background

Recent studies have suggested that stent-grafting may improve the treatment outcome of patients with esophageal perforation, but evidence on this is still lacking.

Methods

Data on 194 patients who underwent conservative (43 patients), endoclip (4 patients) stent-grafting (63 patients) or surgical treatment (84 patients) for esophageal perforation were retrieved from nine medical centers.

Results

In-hospital/30-day mortality was 17.5 %. Three-year survival was 67.1 %. Age, coronary artery disease, and esophageal malignancy were independent predictors of early mortality. Chi squared automatic interaction detection analysis showed that patients without coronary artery disease, without esophageal malignancy and younger than 70 years had the lowest early mortality (4.1 %). Surgery was associated with slightly lower early mortality (conservative 23.3, endoclips 25.0 %, stent-grafting 19.0 %, surgery 13.1 %; p = 0.499). One center reported a series of more than 20 patients treated with stent-grafting which achieved an early mortality of 7.7 % (2/26 patients). Stent-grafting was associated with better survival with salvaged esophagus (conservative 76.7 %, endoclips 75.0 %, stent-grafting 77.8 %, surgery 56.0 %; p = 0.019). Propensity score adjusted analysis showed that stent-grafting achieved similar early mortality (p = 0.946), but significantly higher survival with salvaged esophagus than with surgical treatment (p = 0.001, OR 0.253, 95 % CI 0.110–0.585). Primary surgical repair was associated with somewhat lower early mortality (14.6 vs. 19.0 %; p = 0.561) and better survival with salvaged esophagus (85.4 vs. 77.8 %; p = 0.337) than stent-grafting.

Conclusions

Esophageal perforation was associated with a rather high mortality rate in this all-comers population. Stent-grafting failed to decrease operative mortality, but it improved survival with salvaged esophagus. The results of one of the centers indicate that increasing experience with this less invasive procedure may possibly improve the outcome of these patients.     

Long‐term outcome of intraventricular conduction delays in the general population

BackgroundPrevious population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD).MethodsWe studied long‐term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12‐lead ECG. For left bundle branch block (LBBB) and non‐specific IVCD (NSIVCD), two different definitions were used.ResultsDuring 16.5 years’ follow‐up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04–2.31, p = .032) and 1.27 (95% confidence interval 0.80–2.02, p = .308) for the Strauss’ definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R‐R’ pattern was not associated with any adverse outcome.ConclusionsIn a population study with long‐term follow‐up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder.     

Universal Adhesive for Fixed Retainer Bonding: In Vitro Evaluation and Randomized Clinical Trial

This study aims to assess the efficacy of a universal adhesive (Scotchbond Universal, 3M ESPE) (SB) in total-etch mode, compared to a traditional orthodontic primer (Transbond XT Primer, 3M ESPE) (XT Primer), to perform bonding of orthodontic fixed retainers along with the Transbond XT Light Cure Adhesive Paste (3M ESPE). For the in vitro study, a round section wire (Ortosmail Krugg) was bonded using XT Primer for 20 bovine incisors (Group 1) and SB for other 20 (Group 2). Samples were debonded in a universal testing machine applying a tangential force to specimens (crosshead speed of 1 millimeter per minute). Shear bond strength (SBS) and adhesive remnant index (ARI) scores were calculated. For the in vivo study, 100 patients needing upper and lower canine-to-canine fixed retainers after orthodontic treatment were randomly assigned to two groups of 50 participants each, i.e., group 1 (retainer bonding with XT Primer) and group 2 (retainer bonding with SB). Over two years, examinations were carried out monthly, and detachments were registered by considering the teeth and arches affected. In vitro, no statistically significant differences in SBS and ARI scores were demonstrated between the two groups, both showing a mean bond strength of about 12 MPa and major frequency of ARI “2” (>50% remnant adhesive on the enamel). Conversely, a significantly lower failure rate over 2 years was assessed clinically for group 2 in both arches. Independently of the adhesive and arch, incisors reported a significantly higher failure rate than canines. Scotchbond Universal used in total-etch mode could be a valid alternative to the traditional orthodontic Transbond XT Primer.     

Conventional disease-modifying antirheumatic drugs in early arthritis

This article reviews the use of conventional disease-modifying antirheumatic drugs (DMARDs) in the treatment of early rheumatoid arthritis (RA). The Finnish early RA cohorts are used as examples of how early and active treatment strategies have improved over time with increasing variety of available DMARDs. Therapy goals of early RA include remission to prevent severe long-term outcomes of RA. Remission can be achieved in a third of patients with early RA using a combination of conventional DMARDs, including methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone. Of patients with early RA, 20% to 30% do not improve enough with conventional treatments and should be identified at early phases to consider institution of biologic agents.     

Gene therapy cures the anemia and lethal bone marrow failure in a mouse model of RPS19-deficient Diamond-Blackfan anemia

Diamond-Blackfan anemia is a congenital erythroid hypoplasia caused by functional haploinsufficiency of genes encoding ribosomal proteins. Mutations involving the ribosomal protein S19 gene are detected in 25% of patients. Enforced expression of ribosomal protein S19 improves the overall proliferative capacity, erythroid colony-forming potential and erythroid differentiation of hematopoietic progenitors from ribosomal protein S19-deficient patients in vitro and in vivo following xenotransplantation. However, studies using animal models are needed to assess the therapeutic efficacy and safety of the viral vectors. In the present study we have validated the therapeutic potential of gene therapy using mouse models of ribosomal protein S19-deficient Diamond-Blackfan anemia. Using lentiviral gene transfer we demonstrated that enforced expression of ribosomal protein S19 cures the anemia and lethal bone marrow failure in recipients transplanted with ribosomal protein S19-deficient cells. Furthermore, gene-corrected ribosomal protein S19-deficient cells showed an increased pan-hematopoietic contribution over time compared to untransduced cells without signs of vector-mediated toxicity. Our study provides a proof of principle for the development of clinical gene therapy to cure ribosomal protein 19-deficient Diamond-Blackfan anemia.     

Characterization of a new fiber-reinforced flowable composite

Odontology - This study aimed to evaluate certain physical properties including surface wear of a new experimental short fiber-reinforced flowable resin composite (SFRC) in comparison with...