Tolvaptan reduces the required amount of albumin infusion in patients with decompensated cirrhosis with uncontrolled ascites : a multicenter retrospective propensity score-matched cohort study.

Background: The aim of this retrospective study was to determine whether tolvaptan treatment reduces the amount of albumin administered, volume of ascites removed, and frequency of paracentesis procedures in patients with decompensated cirrhosis with uncontrolled ascites with conventional diuretics. Patients and methods: The control (C) group included patients treated with conventional diuretics. The tolvaptan (T) group included patients treated with both tolvaptan and conventional diuretics. Both groups were matched according to baseline parameters. The amount of albumin administered, volume of ascites removed, and frequency of paracentesis within 30 days of onset of uncontrolled ascites were compared between the two groups. Results: After matching, 74 patients (C=37, T=37) were included. Baseline parameters (C vs. T group) were as follows: age, 69.5 ± 9.3 vs. 70.4 ± 11.0 years (p = 0.702) ; males, 24 (64.9%) vs. 25 (67.6%) (p = 0.999) ; patients with hepatocellular carcinoma, 17 (45.9%) vs. 18 (48.6%) (p = 0.999) ; serum albumin levels at treatment initiation, 2.76 ± 0.48 vs. 2.73 ± 0.49 g/dL (p = 0.773), and serum creatinine levels at treatment initiation, 1.18 ± 1.23 vs. 1.09 ± 0.48 g/dL (p = 0.679). In the C vs. T groups, respectively, mean amount of albumin administered was 51.0 ± 31.4 vs. 33.4 ± 29.8 g/month (p = 0.016) ; mean volume of ascites removed was 2,905 ± 4,921 vs. 1,824 ± 3,185 mL/month (p = 0.266) ; and mean frequency of paracentesis was 0.92 ± 1.46 vs. 0.89 ± 1.45 procedures (p = 0.937). Conclusions: Tolvaptan reduced the use of albumin infusion in patients with decompensated cirrhosis and was effective and acceptable for uncontrolled ascites.

Development and evaluation of a point-of-care test with a combination of EZ-Fast DNA extraction and real-time PCR and LAMP detection: evaluation using blood samples containing the bovine leukaemia DNA.

Along with progress in globalization of society, the spread of infectious diseases has accelerated worldwide. The deployment of highly sensitive genetic tests is essential for early diagnosis and early containment of potential outbreaks and epidemics, as well as routine surveillance, although tedious and expensive nucleic acid extraction steps represent a major drawback. Here we developed a simple and rapid DNA extraction method, named as an EZ-Fast kit, applicable to the field setting. The kit does not require advanced laboratory equipment or expensive DNA extraction kits and achieves crude DNA extraction within 10 min at extremely low cost and can easily be performed in field settings. When combined with real-time PCR and LAMP analyses, the performance of the POCT, using 183 bovine blood samples, was similar to that of the existing DNA extraction method: 92·5% (135/146) (real-time PCR) and 93·7% (133/142) (LAMP) diagnostic sensitivities, and 100% diagnostic specificities. The developed POCT provides a powerful tool to facilitate on-site diagnosis in a field setting.

Varicella zoster virus as a possible trigger for the development of pityriasis lichenoides et varioliformis acuta: retrospective analysis of our institutional cases.

Although numerous infective agents, including varicella zoster virus (VZV), have been described in association with pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC), none has been identified consistently in these lesions. We sought to immunohistochemically identify VZV glycoprotein (g)E antigens in the vascular endothelium in PLEVA and PLC lesions, based on our previous observation that gE was detected in the vascular endothelium and eccrine unit up until 2 months and 2.5, respectively, years after herpes zoster (HZ) infection. In five of the six cases of PLEVA, VZV gE was identified in the endothelial cells and eccrine epithelium, as observed in HZ lesions, whereas VZV gE was detected in only one of seven patients with PLC. None of the patients with PLEVA who had VZV gE-positive vascular endothelial cells had experienced previous episodes of HZ. VZV may be one of the aetiological agents for PLEVA while other aetiological factors could exist in PLC.

Lichen amyloidosus as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

BACKGROUND: Although a number of pathological processes resulting in amyloid deposition have been described in lichen amyloidosus (LA), no attention has been paid to the involvement of sweat glands/ducts in the pathogenesis of LA. According to recent studies, follicular structures are usually spared in serial histological sections of LA, and deposits of amyloid are likely to be confined to areas that display xerosis, suggesting that decreases in skin wetness by sweating disturbance seem to initiate LA. OBJECTIVES: To investigate whether sweating disturbance could represent an early event that triggers LA, and whether resolution of LA could be induced by restoring the sweating disturbance. METHODS: By using the impression mould technique, which allows an accurate quantification of individual sweat glands/ducts actively delivering sweat, we examined sweat responses to thermal stimulus in LA lesions before and after treatment with a moisturizer. RESULTS: Sweating disturbance was most profoundly detected in the 'hub' structure of the LA papule, and this disturbance due to leakage of sweat could be restored by short-term treatment with a moisturizer, particularly when used under occlusion. CONCLUSIONS: This study was limited by the relatively small sample size. Treatment of LA should be primarily directed at preventing leakage of sweat into the dermis or epidermis and therefore sweat delivery to the skin surface could be made easier.

Activation of cerebral sodium-glucose transporter type 1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemia.

The regulation of post-ischemic hyperglycemia plays an important role in suppressing neuronal damage in therapeutic strategies for cerebral ischemia. We previously reported that the cerebral sodium-glucose transporter (SGLT) was involved in the post-ischemic hyperglycemia-induced exacerbation of cerebral ischemic neuronal damage. Cortical SGLT-1, one of the cerebral SGLT isoforms, is dramatically increased by focal cerebral ischemia. In this study, we focused on the involvement of cerebral SGLT-1 in the development of cerebral ischemic neuronal damage. It was previously reported that activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) increases SGLT-1 expression. Moreover, ischemic stress-induced activation of AMPK exacerbates cerebral ischemic neuronal damage. Therefore, we directly confirmed the relationship between cerebral SGLT-1 and cerebral AMPK activation using in vitro primary culture of mouse cortical neurons. An in vivo mouse model of focal cerebral ischemia was generated using a middle cerebral artery occlusion (MCAO). The development of infarct volume and behavioral abnormalities on day 3 after MCAO were ameliorated in cerebral SGLT-1 knock down mice. Cortical and striatal SGLT-1 expression levels were significantly increased at 12h after MCAO. Immunofluorescence revealed that SGLT-1 and the neuronal nuclear antigen (NeuN) were co-localized in the cortex and striatum of MCAO mice. In the in vitro study, primary cortical neurons were cultured for five days before each treatment with reagents. Concomitant treatment with hydrogen peroxide and glucose induced the elevation of SGLT-1 and phosphorylated AMPK/AMPK ratio, and this elevation was suppressed by compound C, an AMPK inhibitor in primary cortical neurons. Moreover, compound C suppressed neuronal cell death induced by concomitant hydrogen peroxide/glucose treatment in primary cortical neurons. Therefore, we concluded that enhanced cerebral SGLT-1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage. One of the mechanisms of cerebral SGLT-1 up-regulation may be involved in the AMPK activation after cerebral ischemia.

Detection of varicella-zoster virus antigens in lesional skin of zosteriform lichen planus but not in that of linear lichen planus.

BACKGROUND: Distinctions between 'linear lichen planus' (LP) and 'zosteriform LP' are difficult to determine solely based on clinical findings. OBJECTIVE: The aim of this study is to determine whether the presence of the varicella-zoster virus (VZV) antigens could be used to differentiate the zosteriform LP from the linear LP. METHODS: We immunohistochemically investigated the presence of in vivo localization of VZV antigens in 8 LP lesions (zosteriform LP: n = 5, linear LP: n = 3). RESULTS: We describe 2 cases of zosteriform LP without apparent prior episodes of herpes zoster, in whom VZV antigens were detected in the eccrine epithelium. Further analysis showed that VZV antigens were exclusively detected in the eccrine epithelium in the zosteriform LP lesions, but not in the linear LP lesions. CONCLUSION: Etiological differences exist between zosteriform LP and linear LP. The presence of VZV antigens in lesional skin of the former indicates a possible triggering role of this virus in the pathogenesis of this variant.

Three-dimensional patterns of early acetabular cartilage damage in hip dysplasia; a high-resolutional CT arthrography study.

OBJECTIVE: The purpose of this study was to examine the three-dimensional (3D) progression patterns of early acetabular cartilage damage in hip dysplasia using high-resolutional computed tomography (CT) arthrography. DESIGN: Thirty-two dysplastic hips of 26 Japanese symptomatic females including 21 hips in pre-stage of osteoarthritis (Kellgren-Lawrence (K-L) grade 0; mean patient age, 32.0 years) and 11 hips in early stage of osteoarthritis (K-L grade 1 or 2; mean patient age, 32.8 years) were examined. Isotropic high-resolutional CT arthrography with an image resolution of 0.5 mm in any orthogonal direction was performed. A 3D acetabular cartilage model was generated and we evaluated distribution of cartilage thickness in 12 zones after dividing the weight-bearing area of the hip joint in radial and lateral/medial directions. RESULTS: In pre-stage of osteoarthritis, significant differences in cartilage thickness were observed between the lateral and medial zones in all radial regions, most prominently in the antero-superior region. In early stage of osteoarthritis, no significant differences in cartilage thickness were observed, except in the most posterior region. The lateral-medial (LM) ratio was defined as cartilage thickness in the lateral zone divided by that in the medial zone, and hips with the LM ratio in the antero-superior region of <1.4 had significantly more extensive involvement of labral tears than hips with the LM ratio of ≥1.4. CONCLUSIONS: In hip dysplasia, acetabular cartilage damage was probably occurred in the antero-superior lateral area. The LM ratio may be a sensitive index to quantify early cartilage damage associated with extent of labral disorders.

Anti-apoptotic function of Xbp1 as an IL-3 signaling molecule in hematopoietic cells.

Cytokine signaling is critical for proliferation, survival and differentiation of hematopoietic cell, and interleukin-3 (IL-3) is required for maintenance of many hematopoietic cell lines, such as BaF3. We have isolated apoptosis-resistant clones of BaF3 using retroviral insertional mutagenesis and the Xbp1 locus was identified as a retroviral integration site. Expression and splicing of the Xbp1 transcript was conserved in the resistant clone but was promptly disappeared on IL-3 withdrawal in parental BaF3. IL-3 stimulation of BaF3 cells enhanced Xbp1 promoter activity and induced phosphorylation of the endoplasmic reticulum stress sensor protein IRE1, resulting in the increase in Xbp1S that activates unfolded protein response. When downstream signaling from IL-3 was blocked by LY294002 and/or dn-Stat5, Xbp1 expression was downregulated and IRE1 phosphorylation was suppressed. Inhibition of IL-3 signaling as well as knockdown of Xbp1-induced apoptosis in BaF3 cells. In contrast, constitutive expression of Xbp1S protected BaF3 from apoptosis during IL-3 depletion. However, cell cycle arrest at the G1 stage was observed in BaF3 and myeloid differentiation was induced in IL-3-dependent 32Dcl3 cells. Expression of apoptosis-, cell cycle- and differentiation-related genes was modulated by Xbp1S expression. These results indicate that the proper transcriptional and splicing regulation of Xbp1 by IL-3 signaling is important in homeostasis of hematopoietic cells.

Associations between self-assessed masticatory ability and higher brain function among the elderly.

Among the elderly, the quality of higher brain function is a contributing factor in performing activities of daily living. The aim of the study is to elucidate, epidemiologically, associations between mastication and higher brain function. A total of 208 community-dwelling elderly persons, aged 70-74 years, were enrolled. Self-assessed masticatory ability (masticatory ability) was classified into one of three categories: ability to chew all kinds of food, ability to chew only slightly hard food, or ability to chew only soft or pureed food. Brain function was assessed by four neuropsychological tests: Raven's Colored Progressive Matrices (RCPM) test, the Verbal Paired Associates 1 (VerPA) task and the Visual Paired Associates 1 task (from the Wechsler Memory Scale Revised Edition), and the Block Design subtest (from the Wechsler Adult Intelligence Scales-Third Edition). Correlations between masticatory ability and each test were examined using Spearman rank correlation coefficients. Multinominal logistic regression models were conducted with the neuropsychological tests as the dependent variables and masticatory ability as the principal independent variable to adjust for age, gender, educational background, social activity, drinking/smoking habits, chronic medical conditions and dental status. Significant correlations were found between the RCPM test, the VerPA task, the Block Design test and masticatory ability. In multinominal logistic regression models, poor masticatory ability was significantly and independently related to the categories under the mean-s.d. points compared with those of the mean ± s.d. ranges for RCPM test and the VerPA task. Significant associations may exist between mastication and higher brain function among the elderly.

Relationships between perceived chewing ability and muscle strength of the body among the elderly.

The aim of the present study was to elucidate whether self-assessed masticatory ability (masticatory ability) is significantly related to muscle strength of the body evaluated as handgrip strength and skeletal muscle mass of the whole body (kg) (SMM) after adjusting for confounding variables, including, age, gender, height, weight, employment status, type of household, educational background, social interaction, chronic medical conditions, smoking habit, drinking habits and dentition status among the elderly. A total of 381 persons aged 67-74 years were enrolled. Masticatory ability was classified into one of three categories: ability to chew all kinds of food, ability to chew only slightly hard food or ability to chew only soft or pureed food. Handgrip strength was measured, and bioimpedance analysis was used to estimate SMM. One-way analysis of variance and Bonferroni methods were used to examine differences in handgrip strength and SMM among the three groups of masticatory ability. An ordinal regression model was conducted with masticatory ability as the dependent variable and handgrip strength as the principal independent variable. Handgrip strength was significantly lower in those individuals who could chew only soft or pureed food than in those individuals who could chew all kinds of food. No significant difference in SMM was found among the three groups of masticatory ability. Masticatory ability was significantly related to handgrip strength after adjusting for SMM, dentition status and background factors. Chewing ability may be related to muscle strength of the body evaluated as handgrip strength, but not evaluated as SMM.

Identification of a new adhesin-like protein from Lactobacillus mucosae ME-340 with specific affinity to the human blood group A and B antigens.

AIMS: To identify and characterize a new adhesin-like protein of probiotics that show specific adhesion to human blood group A and B antigens. METHODS AND RESULTS: Using the BIACORE assay, the adhesion of cell surface components obtained from four lactobacilli strains that adhered to blood group A and B antigens was tested. Their components showed a significant adhesion to A and B antigens when compared to the bovine serum albumin (BSA) control. The 1 mol l(-1) GHCl fraction extracted from Lactobacillus mucosae ME-340 contained a 29-kDa band (Lam29) using SDS-PAGE. The N-terminal amino acid sequence and homology analysis showed that Lam29 was 90% similar to the substrate-binding protein of the ATP-binding cassette (ABC) transporter from Lactobacillus fermentum IFO 3956. The complete nucleotide sequence (858 bp) of Lam29 was determined and encoded a protein of 285 amino acid residues. Phylogenetic analysis and multiple sequence alignments indicated this protein may be related to the cysteine-binding transporter. CONCLUSIONS: The adhesion of ME-340 strain to blood group A and B antigens was mediated by Lam29 that is a putative component of ABC transporter as an adhesin-like protein. SIGNIFICANCE AND IMPACT OF THE STUDY: Lactobacillus mucosae ME-340 expressing Lam29 may be useful for competitive exclusion of pathogens via blood group antigen receptors in the human gastrointestinal mucosa and in the development of new probiotic foods.

Tight junction-based epithelial microenvironment and cell proliferation.

Belt-like tight junctions (TJs), referred to as zonula occludens, have long been regarded as a specialized differentiation of epithelial cell membranes. They are required for cell adhesion and paracellular barrier functions, and are now thought to be partly involved in fence functions and in cell polarization. Recently, the molecular bases of TJs have gradually been unveiled. TJs are constructed by TJ strands, whose basic frameworks are composed of integral membrane proteins with four transmembrane domains, designated claudins. The claudin family is supposedly composed of at least 24 members in mice and humans. Other types of integral membrane proteins with four transmembrane domains, namely occludin and tricellulin, as well as the single transmembrane proteins, JAMs (junctional adhesion molecules) and CAR (coxsackie and adenovirus receptor), are associated with TJ strands, and the high-level organization of TJ strands is likely to be established by membrane-anchored scaffolding proteins, such as ZO-1/2. Recent functional analyses of claudins in cell cultures and in mice have suggested that claudin-based TJs may have pivotal functions in the regulation of the epithelial microenvironment, which is critical for various biological functions such as control of cell proliferation. These represent the dawn of 'Barriology' (defined by Shoichiro Tsukita as the science of barriers in multicellular organisms). Taken together with recent reports regarding changes in claudin expression levels, understanding the regulation of the TJ-based microenvironment system will provide new insights into the regulation of polarization in the respect of epithelial microenvironment system and new viewpoints for developing anticancer strategies.

In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption.

BACKGROUND: Although a severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN), subsequent evolution of the two conditions is quite different. It remains unknown, however, which factors determine whether these lesions resolve spontaneously or subsequently progress to TEN. OBJECTIVES: Because epidermal injury in TEN can be locally reproduced in the evolving FDE lesions, we sought to investigate how epidermal damage can be induced in the evolving FDE lesions and how disease progression to TEN can be prevented, by analysing the FDE lesions induced by clinical challenge with the causative drug. METHODS: We immunohistochemically investigated in vivo dynamics of T-cell trafficking and activation that occur in the evolving FDE lesions using sequential biopsy specimens obtained at multiple time points from the FDE lesions. RESULTS: Intraepidermal CD8+ T cells, which are resident in the lesional epidermis as a stable homogeneous population of memory T cells, transiently acquire a natural killer-like phenotype and express cytotoxic granules upon activation. The influx into the epidermis of CD4+ T cells including Foxp3+ regulatory T cells (Tregs) during the evolution serves to ameliorate epidermal damage induced by activation of the intraepidermal CD8+ T cells. Interleukin-15 derived from the lesional epidermis could maintain the survival of the intraepidermal CD8+ T cells even in the absence of antigenic stimulus over a prolonged period of time (> 4 years). CONCLUSIONS: Whether Tregs could migrate to the lesions upon activation of intraepidermal CD8+ T cells would determine whether the inflammation becomes resolved spontaneously or progresses to TEN.

Long-term interleukin-1alpha treatment inhibits insulin signaling via IL-6 production and SOCS3 expression in 3T3-L1 adipocytes.

Proinflammatory cytokines are well-known to inhibit insulin signaling to result in insulin resistance. IL-1alpha is also one of the proinflammatory cytokines, but the mechanism of how IL-1alpha induces insulin resistance remains unclear. We have now examined the effects of IL-1alpha on insulin signaling in 3T3-L1 adipocytes. Prolonged IL-1alpha treatment for 12 to 24 hours partially decreased the protein levels as well as the insulin-stimulated tyrosine phosphorylation of IRS-1 and Akt phosphorylation. mRNA for SOCS3, an endogenous inhibitor of insulin signaling, was dramatically augmented 4 hours after IL-1alpha treatment. Concomitantly, the level of IL-6 in the medium and STAT3 phosphorylation were increased by the prolonged IL-1alpha treatment. Addition of anti-IL-6 neutralizing antibody to the medium or overexpression of dominant-negative STAT3 decreased the IL-1alpha-stimulated STAT3 activation and SOCS3 induction, and ameliorated insulin signaling. These results suggest that the IL-1alpha-mediated deterioration of insulin signaling is largely due to the IL-6 production and SOCS3 induction in 3T3-L1 adipocytes.

[Durability of aortic root preservation using gelatin-resorcin-formalin glue in acute type A aortic dissection].

During the last 9 years, aortic root preservation using gelatin-resorcin-formalin (GRF) glue was performed in 63 patients as a part of surgery for acute type A aortic dissection. Residual aortic regurgitation (AR) was evaluated, grading 0 to IV+ by echocardiography. The survival and root reoperation-free rates were also assessed. The operative mortality was 9.5% (6 patients). Early postoperative AR < or = I+, = II+ and > or =III+ were 93, 7 and 0%, respectively. Late postoperative AR > or =III+ was observed in 4 patients. Root reoperation was performed in 4 patients (7.0%). In a case of reoperation, medial degeneration was found in the aortic wall, suggesting toxic effect of GRF glue. The actuarial survival and root reoperation-free rates at 9 years were 73 and 80%, respectively. In conclusion, aortic root preservation with the proper use of GRF glue has long-term durability with very low adverse effect.

Interleukin-6 is a candidate molecule that transmits inflammatory information to the CNS.

Peripheral inflammation induces reactions within the CNS such as central sensitization, which is involved in the mechanism of inflammatory hyperalgesia. However, the precise mechanism of inflammatory signal transmission from the peripheral inflammatory site to the CNS is not clear. We studied the role of circulating interleukin (IL)-6 as a messenger of inflammatory information from the periphery to the CNS. In the rat model of inflammatory hyperalgesia induced by carrageenan, levels of IL-6 but not IL-1beta or tumor necrosis factor alpha (TNFalpha) were significantly elevated in the circulating blood 3 h after an injection of carrageenan. In addition, injecting carrageenan into the hind paw evoked thermal hyperalgesia and the release of prostaglandin E(2) (PGE(2)) from isolated blood vessels of the CNS ex vivo, as well as the induction of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) in vascular endothelial cells of the CNS. A prior i.p. injection of IL-6 antiserum (IL-6AS) abolished or attenuated these responses. The present results suggested that circulating IL-6 could act as a messenger of inflammatory information from peripheral inflammatory sites to the CNS and as the afferent circulating signal to the CNS to produce prostaglandins in the vascular endothelial cells of the CNS through a COX-2 dependent pathway.

Effective bone engineering with periosteum-derived cells.

Bone augmentation via tissue engineering has generated significant interest. We hypothesized that periosteum-derived cells could be used in place of bone marrow stromal cells (which are widely used) in bone engineering, but the differences in osteogenic potential between these 2 cell types are unclear. Here, we compared the osteogenic potential of these cells, and investigated the optimal osteoinductive conditions for periosteum-derived cells. Both cell types were induced, via bFGF and BMP-2, to differentiate into osteoblasts. Periosteal cells proliferated faster than marrow stromal cells, and osteogenic markers indicated that bone marrow stromal cells were more osteogenic than periosteal cells. However, pre-treatment with bFGF made periosteal cells more sensitive to BMP-2 and more osteogenic. Transplants of periosteal cells treated with BMP-2 after pre-treatment with bFGF formed more new bone than did marrow stromal cells. Analysis of these data suggests that combined treatment with bFGF and BMP-2 can make periosteum a highly useful source of bone regeneration.