Suppressor of cytokine signal 3 and IL28 genetic variation predict the viral response to peginterferon and ribavirin

Aim: The aim of this study was to investigate the relationship among the expression of suppressor of cytokine signaling 3 (SOCS 3) in the liver, the SNPs in the IL28B locus, and the outcome of interferon therapy. Methods: Prior to interferon treatment, we immunostained 67 liver specimens from chronic hepatitis C (CHC) patients who were receiving peginterferon alpha‐2b/ribavirin therapy for suppressor of cytokine signaling 3 (SOCS3), and compared the expression of SOCS3, IL28 polymorphisms and other clinical factors between the patients and compared their eventual outcomes. Results: Significant differences between the low SOCS3 group and high SOCS3 group were found in age, as well as in the platelet, transaminase, gamma‐glutamyl transpeptidase levels. The incidence of high SOCS3 was not significantly different between subjects with the TT genotype and the TG genotype (TT : TG = 71%:29%, P = 0.250). In a multivariate analysis, age (≥65 years old) (odds ratio 0.221 [0.120–0.966], P = 0.045), IL28B gene (genotype TT) (odds ratio 5.422 [1.254–23.617], P = 0.024) and SOCS3 (high) (odds ratio 0.308 [0.104–0.948], P = 0.040) were significant predictors of the interferon response. In patients with the TT genotype, those with low SOCS3 immunostaining showed a high sustained virological response (69%), while the sustained virological rate was low (27%) in the patients with high SOCS3 immunostaining. Conclusions: Using a combination of the SOCS3 immunostained area in the liver and the expression of IL28B single nucleotide polymorphisms might be a useful predictor of hepatitis C virus clearance by interferon therapy.     

Clinical application of stress-breaking ball attachment for implant overdenture

PatientThe patient was a 62-year-old partially edentulous woman with missing bilateral premolars and molars in the mandibular jaw. The patient selected implant supported-removable partial denture rehabilitation. Implants were placed bilaterally at the distal extension of the denture base in order to minimize denture displacement. The stress-breaking ball (SBB) attachment consists of a flat-top ball head male and O-ring rubber female. The female was covered by a silicone housing with three amounts of space to allow three kinds of settlement (0.3 mm, 0.5 mm, and 0.7 mm); they were selected by thickness or pressure displacement of the mucosa and occlusal force. After the healing period, the SBB attachments (0.3 mm) were placed on the implants, and the implant-supported removable partial denture was then conventionally fabricated. The delivered denture had sufficient retention and appropriate stress breaking.DiscussionThe advantages of SBB attachments over conventional attachments are as follows: (1) they prevent the implant from excessive occlusal force, (2) they are ready-made, (3) they show appropriate retention, and (4) they can be easily mounted on the denture base. The disadvantages of these attachments are as follows: (1) they are approximately 1 mm higher than conventional ball attachments and (2) the retentive force cannot be adjusted.ConclusionThe use of a stress-breaking attachment for implant overdenture rehabilitation should be considered so that the occlusal force is equally distributed between the alveolar ridge and the implants.     

Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours

The purpose of the current study was to investigate the mutation status of KIT in feline mast cell tumours (MCTs) and to examine the effects of tyrosine kinase inhibition on the phosphorylation of mutant kit in vitro and in clinical cases of cats. Sequence analysis of KIT identified mutations in 42/62 MCTs (67·7%). The vast majority of the mutations were distributed in exons 8 and 9, both of which encode the fifth immunoglobulin-like domain (IgD) of kit. All five types of kit with a mutation in the fifth IgD were then expressed in 293 cells and examined for phosphorylation status. The mutant kit proteins showed ligand-independent phosphorylation. The tyrosine kinase inhibitor imatinib mesylate suppressed the phosphorylation of these mutant kit proteins in transfectant cells. In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells. Mutations in the fifth IgD of kit thus appear to be common and potentially sensitive to imatinib mesylate in feline MCTs. These data provide an in vivo model for paediatric mastocytosis where mutations in the fifth IgD of kit also occur.     

Effects of caloric restriction on the kinetics of indocyanine green in patients with liver diseases and in the rat

The effect of caloric restriction on the hepatic uptake and excretion of indocyanine green (ICG) was studied in man as well as in rats. It was demonstrated that following a 72-hr caloric restriction in man, the plasma clearance rate for ICG was increased significantly at the low dose of 0.5 mg/kg, and transport maximum was increased without a significant change of storage capacity. In rats, the maximal biliary excretion was significantly increased after 48-hr fast, but neither maximal hepatic uptake (V _max) nor hepatic ICG content was altered. The evidence is consistent with the view that fasting increases the ICG plasma clearance at low doses by enhancement of excretory steps at the bile canalicular membrane.     

Is blood pressure during the night more predictive of cardiovascular outcome than during the day?

The objective of this study was to investigate the prognostic significance of the ambulatory blood pressure (BP) during night and day and of the night-to-day BP ratio (NDR). We studied 7458 participants (mean age 56.8 years; 45.8% women) enrolled in the International Database on Ambulatory BP in relation to Cardiovascular Outcome. Using Cox models, we calculated hazard ratios (HR) adjusted for cohort and cardiovascular risk factors. Over 9.6 years (median), 983 deaths and 943 cardiovascular events occurred. Nighttime BP predicted mortality outcomes (HR, 1.18-1.24; P<0.01) independent of daytime BP. Conversely, daytime systolic (HR, 0.84; P<0.01) and diastolic BP (HR, 0.88; P<0.05) predicted only noncardiovascular mortality after adjustment for nighttime BP. Both daytime BP and nighttime BP consistently predicted all cardiovascular events (HR, 1.11-1.33; P<0.05) and stroke (HR, 1.21-1.47; P<0.01). Daytime BP lost its prognostic significance for cardiovascular events in patients on antihypertensive treatment. Adjusted for the 24-h BP, NDR predicted mortality (P<0.05), but not fatal combined with nonfatal events. Participants with systolic NDR of at least 1 compared with participants with normal NDR (> or = 0.80 to <0.90) were older, at higher risk of death, but died at higher age. The predictive accuracy of the daytime and nighttime BP and the NDR depended on the disease outcome under study. The increased mortality in patients with higher NDR probably indicates reverse causality. Our findings support recording the ambulatory BP during the whole day.     

Secure and effective gene delivery system of plasmid DNA coated by polynucleotide

Polynucleotides are anionic macromolecules which are expected to transfer into the targeted cells through specific uptake mechanisms. So, we developed polynucleotides coating complexes of plasmid DNA (pDNA) and polyethylenimine (PEI) for a secure and efficient gene delivery system and evaluated their usefulness. Polyadenylic acid (polyA), polyuridylic acid (polyU), polycytidylic acid (polyC), and polyguanylic acid (polyG) were examined as the coating materials. pDNA/PEI/polyA, pDNA/PEI/polyU, and pDNA/PEI/polyC complexes formed nanoparticles with a negative surface charge although pDNA/PEI/polyG was aggregated. The pDNA/PEI/polyC complex showed high transgene efficiency in B16-F10 cells although there was little efficiency in pDNA/PEI/polyA and pDNA/PEI/polyU complexes. An inhibition study strongly indicated the specific uptake mechanism of pDNA/PEI/polyC complex. Polynucleotide coating complexes had lower cytotoxicity than pDNA/PEI complex. The pDNA/PEI/polyC complex showed high gene expression selectively in the spleen after intravenous injection into mice. The pDNA/PEI/polyC complex showed no agglutination with erythrocytes and no acute toxicity although these were observed in pDNA/PEI complex. Thus, we developed polynucleotide coating complexes as novel vectors for clinical gene therapy, and the pDNA/PEI/polyC complex as a useful candidate for a gene delivery system.