Sofosbuvir-based therapy for patients with chronic hepatitis C: Early experience of its efficacy and safety in Korea

Background/Aims

The previous standard treatment for chronic hepatitis C (CHC) patients, comprising a combination of pegylated interferon (IFN) and ribavirin, was associated with suboptimal efficacy and severe adverse reactions. A new era of direct-acting antivirals is now dawning in Korea. Early experience of applying sofosbuvir-based therapy to CHC patients in Korea is reported herein.

Methods

Data on efficacy and safety were collected for CHC patients treated with a combination of sofosbuvir plus ribavirin or sofosbuvir/ledipasvir with or without ribavirin.

Results

This retrospective study included 25 consecutive patients who received sofosbuvir-based therapy (19 with genotype 1b and 6 with genotype 2) at Seoul National University Hospital from May 2014 to April 2015. A virologic response was achieved at week 4 by 85.7% and 80% of the patients with genotypes 1b and 2, respectively. The HCV-RNA level decreased more slowly in IFN-experienced than in treatment-naïve patients with genotype 1b. However, the sustained virologic response at week 12 (SVR12) rate did not differ among these patients, and was as high as 100%. The presence of cirrhosis significantly increased the risk of a virologic response failure at week 4 (OR, 11.0; P=0.011) among patients with HCV genotype 1b. Only five patients (20%) experienced minor adverse events, including grade 1 fatigue and headache. The hemoglobin level decreased slightly after sofosbuvir-based therapy, but there was no case of premature discontinuation of this therapy.

Conclusions

In a real clinical practice, sofosbuvir-based therapy for CHC patients in Korea achieved optimal antiviral efficacy with insignificant adverse events. Long-term follow-up data are warranted to ensure the sustained antiviral efficacy and long-term safety of sofosbuvir-based IFN-free therapy.     

Primary headaches interfere with the efficacy of temporomandibular disorders management

OBJECTIVES:

This cross-sectional study aimed to evaluate the influence of Primary Headache (PH) on efficacy of a Temporomandibular Disorders (TMD) conservative therapy and its association with the presence of self-reported parafunctional habits.

SAMPLE AND METHODS:

Sample was composed of 400 medical records, divided into four groups: I) Muscular TMD (n=64); II) Muscular TMD+PH (n=48); III) Muscular TMD+Articular TMD (n=173); IV) Muscular TMD+Articular TMD+PH (n=115). All groups had undergone a TMD therapy for three months with a stabilization appliance and counseling for habits and behavioral changes, with no specific headache management. Current pain intensity and existence or not of self-reported bruxism were assessed. Repeated measures ANOVA and Chi-Square test followed by Odds were used for statistical analysis, with a significance level of 5%.

RESULTS:

results of this study showed that: (1) A conservative therapy with stabilization appliance and counseling for habits and behavioral changes was effective in the TMD pain relief; (2) Groups with an additional diagnosis of PH had worsened the pain improvement significantly; and (3) no association between the presence of self-reported bruxism and PH was found.

CONCLUSIONS:

this study could elucidate the important effect that headache may have on the TMD management.     

Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses

Resolvin E1 (RvE1) is a lipid mediator derived from ω3 polyunsaturated fatty acids that exerts potent antiinflammatory roles in several murine models. The antiinflammatory mechanism of RvE1 in acquired immune responses has been attributed to attenuation of cytokine production by dendritic cells (DCs). In this study, we newly investigated the effect of RvE1 on DC motility using two-photon microscopy in a contact hypersensitivity (CHS) model and found that RvE1 impaired DC motility in the skin. In addition, RvE1 attenuated T cell priming in the draining lymph nodes and effector T cell activation in the skin, which led to the reduced skin inflammation in CHS. In contrast, leukotriene B4 (LTB4) induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. Collectively, our results suggest that RvE1 attenuates cutaneous acquired immune responses by inhibiting cutaneous DC motility, possibly through LTB4-BLT1 signaling blockade.Following the well-known epidemiological study conducted in Northwest Greenland in the 1970s (Dyerberg et al., 1978), several clinical assessments have indicated that a diet rich in ω3 polyunsaturated fatty acids (PUFAs) has beneficial effects in various inflammatory diseases, including asthma, psoriasis, inflammatory bowel diseases, and rheumatoid arthritis (Horrobin, 1987). Although it remains unclear how ω3 PUFAs exert such antiinflammatory effects, recent studies have identified several derivatives of ω3 PUFAs that possess strong antiinflammatory effects (Serhan et al., 2008; Tull et al., 2009). Resolvin E1 (RvE1) is one such antiinflammatory lipid mediator.RvE1 is known to exert its actions through two receptors, BLT1 and ChemR23 (Arita et al., 2007). RvE1 binds to BLT1, a G protein–coupled receptor for leukotriene B4 (LTB4), and inhibits BLT1 signals (Arita et al., 2007). In addition, RvE1 exhibits an agonistic activity toward ChemR23 (Arita et al., 2007), a G protein–coupled receptor for chemerin. The antiinflammatory effects of RvE1 have been demonstrated in acute innate immune inflammation, such as peritonitis (Arita et al., 2007) and colitis (Arita et al., 2005b). In these models, RvE1 exerted its antiinflammatory effects by inhibiting neutrophil infiltration into the inflammatory foci through a blockade of LTB4-BLT1 signaling in neutrophils (Haas-Stapleton et al., 2007). In contrast, few studies have been conducted on the effect of RvE1 on acquired immune responses, in which DCs and T cells play major roles in the development. In these studies, the attenuated cytokine production, such as IL-12 and IL-23, from DCs is considered as the major mechanism by which RvE1 exerts the antiinflammatory effects (Arita et al., 2005a; Haworth et al., 2008). However, the effect of RvE1 on DC motility has not been investigated in the context of acquired immunity.In the peripheral tissues such as the skin, DCs migrate in an amoeboid movement that requires actin polymerization via activation of the Rho family of small GTPases, such as Cdc42, Rac, and Rho A (Lämmermann and Germain, 2014). In acquired immunity such as contact hypersensitivity (CHS), upon uptake of foreign antigens, DCs migrate to the draining LNs (dLNs) via lymphatic vessels to establish sensitization by inducing the antigen-specific T cell differentiation (Honda et al., 2013). In elicitation, DC migration to form DC–T cell clustering is required for efficient antigen presentation in situ (Natsuaki et al., 2014). Thus, active DC motility is an essential factor for acquired immunity.In this study, we investigated the effects and underlying mechanisms of RvE1 on DC motility using a CHS model, which is a prototype of delayed-type hypersensitivity in the skin mediated by IFN-γ (Mori et al., 2008; Honda et al., 2013). RvE1 inhibited cutaneous DC migration into the dLNs and suppressed antigen-specific T cell induction in the sensitization phase. In addition, live imaging analysis revealed that RvE1 inhibited cutaneous DC motility and cluster formation in the skin, which subsequently attenuated activation of effector T cells in the skin in the elicitation phase of CHS. Intriguingly, LTB4 induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. These results suggest that RvE1 exerts its antiinflammatory effects in cutaneous acquired immunity by inhibiting DC motility, possibly through an LTB4-BLT1 signaling blockade.     

The Heart Failure Association Atlas: rationale,objectives, and methods

Heart failure (HF) constitutes the growing cardiovascular burden and the major public health issue, but comprehensive statistics on HF epidemiology and related management in Europe are missing. The Heart Failure Association (HFA) Atlas has been initiated in 2016 in order to close this gap, representing the continuity directly rooted in the European Society of Cardiology (ESC) Atlas of Cardiology. The major aim of the HFA Atlas is to establish a contemporary dataset on HF epidemiology, resources and reimbursement policies for HF management, organization of the National Heart Failure Societies (NHFS) and their major activities, including education and HF awareness. These data are gathered in collaboration with the network of NHFS of the ESC member and ESC affiliated countries. The dataset will be continuously improved and advanced based on the experience and enhanced understanding of data collection in the forthcoming years. This will enable revealing trends, disparities and gaps in knowledge on epidemiology and management of HF. Such data are highly needed by the clinicians of different specialties (aside from cardiologists and cardiac surgeons), researchers, healthcare policy makers, as well as HF patients and their caregivers. It will also allow to map the snapshot of realities in HF care, as well as to provide insights for evidence‐based health care policy in contemporary management of HF. Such data will support the ESC/HFA efforts to improve HF management ant outcomes through stronger recommendations and calls for action. This will likely influence the allocation of funds for the prevention, treatment, education and research in HF.     

Chromosome size-correlated and chromosome size-uncorrelated homogenization of centromeric repetitive sequences in New World quails

Many families of centromeric repetitive DNA sequences isolated from Struthioniformes, Galliformes, Falconiformes, and Passeriformes are localized primarily to microchromosomes. However, it is unclear whether chromosome size-correlated homogenization is a common characteristic of centromeric repetitive sequences in Aves. New World and Old World quails have the typical avian karyotype comprising chromosomes of two distinct sizes, and C-positive heterochromatin is distributed in centromeric regions of most autosomes and the whole W chromosome. We isolated six types of centromeric repetitive sequences from three New World quail species (Colinus virginianus, CVI; Callipepla californica, CCA; and Callipepla squamata, CSQ; Odontophoridae) and one Old World quail species (Alectoris chukar, ACH; Phasianidae), and characterized the sequences by nucleotide sequencing, chromosome in situ hybridization, and filter hybridization. The 385-bp CVI-MspI, 591-bp CCA-BamHI, 582-bp CSQ-BamHI, and 366-bp ACH-Sau3AI fragments exhibited tandem arrays of the monomer unit, and the 224-bp CVI-HaeIII and 135-bp CCA-HaeIII fragments were composed of minisatellite-like and microsatellite-like repeats, respectively. ACH-Sau3AI was a homolog of the chicken nuclear membrane repeat sequence, whose homologs are common in Phasianidae. CVI-MspI, CCA-BamHI, and CSQ-BamHI showed high homology and were specific to the Odontophoridae. CVI-MspI was localized to microchromosomes, whereas CVI-HaeIII, CCA-BamHI, and CSQ-BamHI were mapped to almost all chromosomes. CCA-HaeIII was localized to five pairs of macrochromosomes and most microchromosomes. ACH-Sau3AI was distributed in three pairs of macrochromosomes and all microchromosomes. Centromeric repetitive sequences may be homogenized in chromosome size-correlated and -uncorrelated manners in New World quails, although there may be a mechanism that causes homogenization of centromeric repetitive sequences primarily between microchromosomes, which is commonly observed in phasianid birds.     

A Study of Diphenylfumaronitrile and Furan‐Substituted Diketopyrrolopyrrole Alternating Copolymer and Its Thin‐Film Transistors

A fused aromatic furan‐substituted diketopyrrolopyrrole and novel diphenylfumaronitrile conjugated building blocks are used for the synthesis of an alternating copolymer ( DPFN‐DPPF ) via Suzuki polycondensation. In this paper, the first attempt to use the diphenylfumaro­nitrile building block for the synthesis of conjugated polymer is described. The number‐average and weight‐average ­molecular weights calculated for DPFN‐DPPF are 20 661 and 66 346 g mol^?1, respectively. The optical bandgap calculated for DPFN‐DPPF is 1.53 eV whereas the highest occupied molecular orbital (HOMO) value calculated by photoelectron spectroscopy in air (PESA) is 5.50 eV. The calculated HOMO value is lower, which is suitable for stable organic electronic devices. DPFN‐DPPF polymer is used as an active layer in bottom‐contact bottom‐gate organic thin‐film transistor devices and the thin film exhibits a hole mobility of 0.20 cm² V^?1 s^?1 in air.