Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy

BACKGROUND AND PURPOSE

Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects.

EXPERIMENTAL APPROACH

We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed.

KEY RESULTS

As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias.

CONCLUSIONS AND IMPLICATIONS

Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling.     

Usefulness of ultrasonography for rapidly diagnosing cutaneous sinus tracts of dental origin

Background

Cutaneous sinus tracts of dental origin are frequently misdiagnosed and incorrectly treated. Intraoral roentgenograms are valuable for diagnosing such tracts. Since these lesions are usually not accompanied by dental symptoms, patients tend initially to consult dermatologists or general physicians, who are not familiar with oral diseases or intraoral X-rays.

Objectives

We sought to determine the usefulness of ultrasonography for detecting cutaneous sinus tracts of dental origin.

Materials and methods

Three patients who had skin lesions that were suspected of being cutaneous sinus tracts based on the findings of clinical and histological examinations were enrolled in this study. B mode and color Doppler ultrasonography were used to image the skin lesions in their entirety and to assess the associations between the subcutaneous lesions and any alveolar bone defects.

Results

In each case, ultrasonography depicted a hypoechoic band that originated from the cutaneous lesion and extended through the subcutaneous tissue to the alveolar bone. Bone loss was also observed, and color Doppler ultrasonography detected increased blood flow in the peripheral regions of the tracts.

Conclusions

In the present study, the patients’ sinus tracts were rapidly detected using ultrasonography, which enabled appropriate treatment. Thus, ultrasonography is a convenient tool for diagnosing cutaneous sinus tracts of dental origin.

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A Within-Group Design of Nontreatment Seeking 5-HTTLPR Genotyped Alcohol-Dependent Subjects Receiving Ondansetron and Sertraline

Background: Serotonergic mechanisms are associated with the development of alcohol dependence (AD), however, studies evaluating serotonergic medications have produced conflicting results. One hypothesis suggests that differential response may be due to a functional polymorphism of the 5‐HTTLPR promoter region of the serotonin re‐uptake transporter (5‐HTT). The L/L genotype is postulated to be associated with early onset alcoholism and the S/S or S/L genotypes associated with late onset alcoholism. The aim of this study was to match and mismatch L/L, S/S, or S/L genotypes with administration of ondansetron and sertraline. Methods: Fifteen nontreatment seeking alcohol‐dependent individuals were randomized to 1 of 2 counterbalanced arms to receive either 200 mg/d of sertraline or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self‐administration experiment (ASAE), then received placebo for 3 weeks followed by a second ASAE. Participants then received the alternate drug for 2 weeks followed by a third ASAE. Results: At the first ASAE compared to sertraline, ondansetron significantly improved drinking outcomes for the L/L genotype for the ASAE volume consumed (100% reduction based on between‐subjects comparison, t = 2.35), and for drinks per drinking day during the 7 days prior to the ASAE (79% reduction and t = 4.34). Compared with ondansetron for S/S or S/L genotypes, outcomes at ASAE 1 for sertraline and S/S or S/L genotypes are opposite than hypothesized. Overall, subjects reduced drinking across their participation in the trial, as there appears to be an order effect. Conclusion: This study suggests that ondansetron may reduce alcohol consumption in alcohol‐dependent individuals who have the L/L genotype as measured naturalistically and during the ASAE. By contrast there was no support that sertraline reduces alcohol use in individuals who have S/S or S/L genotypes. Evidence in the literature suggests that AD in some individuals may be influenced by a gene by socio‐environmental interaction making pharmacological treatment with serotonergic drugs complex. Research must consider that typologies may predict successful treatment of AD in future trials.     

Effect of α-tocopherol on carbon tetrachloride intoxication in the rat liver

Carbon tetrachloride (1 ml/kg body weight as a 1:1 mixture of CCl₄ and mineral oil) was orally administered to rats. After 12 h, the activity of plasma ALT (alanine aminotransferase) was significantly higher than that of the control group, and plasma ALT and AST (aspartate aminotransferase) activities significantly increased 24 h after CCl₄ administration. These results indicated that the necrotic process had initiated at about 12 h and developed thereafter. After 6–24 h of CCl₄ administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced 6 h after CCl₄ intoxication and thereafter. Oral administration of vitamin E (1 ml/kg body weight as a 1:1 mixture of α-tocopherol and mineral oil) 12 h before CCl₄ administration caused a significant elevation of liver vitamin E level and ameliorated liver necrosis 24 h after CCl₄ intoxication based on plasma AST and ALT. Vitamin E also significantly restored the hepatic vitamin C concentration 12 and 24 h after CCl₄ intoxication, demonstrating that vitamin E functioned as an antioxidant. The liver vitamin E concentration was not changed by vitamin E supplementation to rats that did not receive CCl₄. This result indicated that vitamin E accumulated in the damaged liver. The activation of JNK, ERK1/2 and p38 MAPK took place 1.5 h after CCl₄ administration. Co-administration of α-tocopherol with CCl₄ did not affect these early changes in MAPKs.     

Tissue engineered epithelial cell sheets for the creation of a bioartificial trachea

To successfully engineer a bioartificial tracheal replacement, it is believed that the regeneration of a functional epithelial lining is a key requirement. In the present study, rabbit tracheal epithelial cells were cultured on temperature-responsive culture dishes, under normal culture conditions at 37 degrees C. By simple temperature reduction to 20 degrees C, the cultured epithelial cells were noninvasively harvested as intact sheets, without the use of any proteolytic enzymes. Support Dacron grafts that had been subcutaneously implanted for 4 weeks to allow for host tissue and vessel infiltration were then opened, and the tracheal epithelial cell sheets were transplanted to the luminal surface without sutures. These fabricated constructs were then used as tracheal replacements, in a rabbit model. Four weeks after transplantation, results showed that the tracheal grafts were covered by a mature, pseudostratified columnar epithelium. In contrast, control constructs that did not receive cell sheet transplantation demonstrated only a thin, immature epithelium at the center of the replacement graft. These results therefore demonstrate that these tracheal epithelial cell sheets can create an epithelial lining on the luminal surface of a bioartificial trachea.     

Efficacy and safety of infliximab: A comparison with other biological disease-modifying anti-rheumatic drugs

Objectives: The intensification of infliximab (IFX) treatment, involving escalation of the dose and shortening of interval, was approved in Japan in July 2009. We consider IFX intensification therapy to be preferable for patients with treatment-resistant active rheumatoid arthritis (RA). We retrospectively compared the efficacy of IFX with that of other bDMARDs in methotrexate (MTX)-resistant patients.

Methods: Patients who satisfied the following criteria were enrolled: (i) those who started bDMARDs between February 2011 and December 2016, and (ii) those who required bDMARDs after 180 d of MTX treatment. We compared 33 patients who had been treated with IFX (IFX group) and 146 who had received other bDMARDs treatment (non-IFX group).

Results: IFX was administered at a dose of 6.98?mg/kg/8-week equivalent at 52 weeks. Clinical disease activity index clinical remission (CDAI-CR) was achieved in 49 of the 179 patients at 52 weeks and 13 of these 49 patients received IFX. Logistic regression analysis showed that treatment with IFX was an important variable for the achievement of CDAI-CR at 52 weeks (odds ratio 2.69, 95% confidence interval 1.13–6.42). The severity and frequency of adverse events did not differ.

Conclusion: Intensification of IFX was effective and well tolerated for MTX resistant patients.     

Evaluation of MR cisternography of the cerebellopontine angle using a balanced fast-field-echo sequence: preliminary findings

We evaluated the feasibility of MR cisternography by the balanced fast-field-echo (bFFE) sequence, comparing with that by a turbo-spin-echo (TSE) sequence, for cerebellopontine angle lesions on a 1.5-T imager (Gyroscan Intera, Philips, Best, The Netherlands). The bFFE MR cisternograms depicted target cranial nerves with less cerebrospinal fluid pulsation artifacts than TSE cisternograms and visualized an acoustic schwannoma in 6 of 44 patients with suspicion and a causative vessel of hemifacial spasm in all of 3 patients in a short scanning time (1 min 53 s). The bFFE sequence can be promising for MR cisternography in the diagnosis of cerebellopontine angle lesions.