Different hypersensitivities against homologous proteins of MGL_1304 in patients with atopic dermatitis

Background

Atopic dermatitis (AD) is exacerbated by sweating, and the skin of most patients with AD are resided by Malassezia (M.) fungi. Recently, MGL_1304 produced by Malassezia globosa was identified as the major histamine releasing antigen in human sweat.

Radical Polymerization and Copolymerization of 12‐[(N‐Methacryloyl)carbamoyloxy]octadecanoic Acid

Radical polymerization of 12‐[(N‐methacryloyl)carbamoyloxy] octadecanoic acid ( 1 ) was kinetically and ESR spectroscopically investigated in acetone, using dimethyl 2,2′‐azobisisobutyrate ( 2 ) as initiator. The polymerization rate (R_p) is given by R_p = k [2]^0.7[1]^1.4 at 50°C. Propagating poly( 1 ) radical was observed as a 13‐lines spectrum by ESR under the actual polymerization conditions. The ESR‐determined k_p values (1.8–7.9 L/mol·s) are much lower than those of usual methacrylate monomers. The rate constant (k_t) of termination was determined to be k_t = 1.0–2.7·10⁴ L/mol·s from decay curve of the propagating radical. The Arrhenius plots of k_p and k_t gave the activation energies of propagation (63 kJ/mol) and termination (24 kJ/mol). A significant solvent effect was observed on the radical polymerization of 1 . The copolymerizations of 1 with styrene(St) and acrylonitrile were examined at 50°C. Copolymerization parameters obtained for the 1  (M₁)/St (M₂) system are as follows; r₁ = 0.73, r₂ = 0.57, Q₁ = 0.83, and e₁ = 0.13.     

Analysis of 5'-end sequences of chimpanzee cDNAs

We constructed full-length enriched cDNA libraries from chimpanzee brain, skin, and liver tissues by the oligo-capping method to establish a database of sequences of chimpanzee genes. Randomly selected clones from the libraries were subjected to one-pass sequencing from their 5'-ends. As a result, we collected 6813 chimpanzee cDNA sequences longer than 400 bp. Homology search against human mRNA sequences (RefSeq mRNAs) revealed that our collection included sequences of 1652 putative chimpanzee genes. In order to calculate the sequence identity between human and chimpanzee homologs, we constructed 5'-end consensus sequences of 226 chimpanzee genes by aligning at least three sequences for individual genes. Sequence identity was estimated by comparing these consensus sequences and the corresponding sequences of their human homologs. The average sequence identity of the 5'-end cDNAs was 99.30%. Those of the 5'-UTRs and CDSs were 98.79% and 99.42%, respectively. The results confirmed that human and chimpanzee genes are highly conserved at the nucleotide level. As for amino acids, the average sequence identity was 99.44%. The average synonymous (K(S)) and nonsynonymous (K(A)) divergences were estimated to be 1.33% and 0.28%, respectively.     

Incidence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection who have normal alanine aminotransferase values

The importance of alanine aminotransferase (ALT) levels in the progression of hepatitis B virus (HBV) infection remains a subject of debate. This study sought to identify independent risk factors involved in development of hepatocellular carcinoma (HCC), particularly in patients with chronic HBV infection who have normal ALT values. Data from 381 consecutive hepatitis B patients were analyzed with average ALT integration values ≤40 IU/L and follow‐up periods of >3 years. Integration values were calculated from biochemical tests, and serological markers associated with the cumulative incidence of HCC were analyzed. HCC developed in 17 of the 381 patients (4.5%) during the follow‐up period. Male sex (hazard ratio, 6.011 [95% confidence interval: 1.353–26.710], P = 0.018), high HBV‐DNA levels (≥5.0 log copies/ml; 5.125 [1.880–13.973], P = 0.001), low platelet counts (<15.0 × 10⁴/mm³; 4.803 [1.690–13.647], P = 0.003), and low total cholesterol levels (<130 mg/dl; 5.983 [1.558–22.979], P = 0.009) were significantly associated with greater incidence of HCC development. High HBV‐DNA levels and low platelet counts are associated with the development of HCC in patients infected with hepatitis B who have normal ALT values. Therefore, maintenance of low HBV‐DNA levels is important for the prevention of HCC in patients with low platelet counts, particularly in patients whose ALT values fall within the current normal range. J. Med. Virol. 82:539–545, 2010. © 2010 Wiley‐Liss, Inc.     

A mutation database for amyotrophic lateral sclerosis

An amyotrophic lateral sclerosis (ALS) mutation database has been constructed as a publicly accessible online resource for recording the nucleotide and amino acid variants identified in genes associated with ALS, along with corresponding clinical conditions. The database currently consists of more than 600 entries, including about 180 unique variants found in 25 disease‐causative or disease‐related genes. In addition to published data collected from literature, novel variants identified by microarray resequencing in our laboratory are incorporated into the database. Every reported gene has a respective page that provides information on its variation positions with various statistics, clinical characteristics, and primary references, as well as gene‐sequence and protein‐structure information that will assist in assessing variation significance. Users can access a homology search function to find variations in arbitrary sequences of interest and to check if they have already been described in the database. This database is expected to fulfill an essential need in terms of integrating comprehensive information on genetic and clinical data related to ALS, which will subsequently deepen our understanding of the possible mechanisms of the disease, as well as help with the clinical practice and treatment of ALS. The database is accessible at: https://reseq.lifesciencedb.jp/resequence/SearchDisease.do?targetId=1 . Data submission is open to all researchers and is highly encouraged. Hum Mutat 31:1003–1010, 2010. © 2010 Wiley‐Liss, Inc.     

Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex

Plectin is a cytoskeletal linker protein which has a long central rod and N‐ and C‐terminal globular domains. Mutations in the gene encoding plectin (PLEC) cause two distinct autosomal recessive subtypes of epidermolysis bullosa: EB simplex (EBS) with muscular dystrophy (EBS‐MD), and EBS with pyloric atresia (EBS‐PA). Previous studies have demonstrated that loss of full‐length plectin with residual expression of the rodless isoform leads to EBS‐MD, whereas complete loss or marked attenuation of expression of full‐length and rodless plectin underlies the more severe EBS‐PA phenotype. However, muscular dystrophy has never been identified in EBS‐PA, not even in the severe form of the disease. Here, we report the first case of EBS associated with both pyloric atresia and muscular dystrophy. Both of the premature termination codon‐causing mutations of the proband are located within exon 32, the last exon of PLEC. Immunofluorescence and immunoblot analysis of skin samples and cultured fibroblasts from the proband revealed truncated plectin protein expression in low amounts. This study demonstrates that plectin deficiency can indeed lead to both muscular dystrophy and pyloric atresia in an individual EBS patient. © 2010 Wiley‐Liss, Inc.     

Mast cell-derived tumor necrosis factor can promote nerve fiber elongation in the skin during contact hypersensitivity in mice

In humans, lesions of contact eczema or atopic dermatitis can exhibit increases in epidermal nerves, but the mechanism resulting in such nerve elongation are not fully understood. We found that contact hypersensitivity reactions to oxazolone in mice were associated with significant increases in the length of nerves in the epidermis and dermis. Using genetically mast cell-deficient c-kit mutant mice selectively repaired of their dermal mast cell deficiency with either wild-type or tumor necrosis factor (TNF)-deficient mast cells, we found that mast cells, and mast cell-derived TNF, significantly contributed to the elongation of epidermal and dermal PGP 9.5+ nerves and dermal CGRP+ nerves, as well as to the inflammation observed at sites of contact hypersensitivity in response to oxazolone. Moreover, the percentage of mast cells in close proximity to dermal PGP 9.5+ nerve fibers was significantly higher in wild-type mice and in c-kit mutant mice repaired of their dermal mast cell deficiency by the adoptive transfer of wild-type mast cells than in TNF-deficient mice or in TNF-/- mast cell-engrafted c-kit mutant mice. These observations show that mast cells, and mast cell-derived TNF, can promote the elongation of cutaneous nerve fibers during contact hypersensitivity in the mouse.     

Role of small airways in asthma: investigation using high-resolution computed tomography

BACKGROUND: Small airways may have an important role in asthma but are more difficult to assess pathologically than central airways. Computed tomographic indices of lung density are assumed to reflect air trapping and may be a useful noninvasive measure of small airways disease, but their pathophysiological relevance remains undetermined. OBJECTIVE: To evaluate lung density on high-resolution computed tomography and examine its correlations with clinical and physiologic variables in 29 patients with stable asthma. METHODS: Both lungs were scanned at full-inspiratory and full-expiratory phases to quantify percentage of lung field occupied by low attenuation area (LAA%; < -960 Hounsfield units) and mean lung density. Asthma severity, pulmonary function, methacholine airway sensitivity and reactivity, and sputum eosinophil counts were evaluated. RESULTS: The mean lung density increased and LAA% decreased in all patients at expiratory phase compared with inspiratory phase. The inspiratory density indices and expiratory mean lung density correlated only with FEV(1)/forced vital capacity (FVC). Expiratory LAA% correlated more strongly than other variables with FEV(1)/FVC and with indices of peripheral airflow obstruction. Expiratory/inspiratory ratios of LAA% and mean lung density correlated, the former more strongly, with disease severity, residual volume/total lung capacity, and airway sensitivity, as well as with indices of global (FEV(1) and FEV(1)/FVC) and peripheral airflow obstruction. CONCLUSION: Expiratory/inspiratory high-resolution computed tomography is useful for assessing small airways disease in asthma. Small airways involvement is associated with airflow obstruction, airway hypersensitivity, and more severe disease. CLINICAL IMPLICATIONS: Small airways are an important therapeutic target in asthma.     

Chronically increased transforming growth factor-beta1 strongly inhibits hippocampal neurogenesis in aged mice

There is increasing evidence that hippocampal learning correlates strongly with neurogenesis in the adult brain. Increases in neurogenesis after brain injury also correlate with improved outcomes. With aging the capacity to generate new neurons decreases dramatically, both under normal conditions and after injury. How this decrease occurs is not fully understood, but we hypothesized that transforming growth factor (TGF)-beta1, a cell cycle regulator that rapidly increases after injury and with age, might play a role. We found that chronic overproduction of TGF-beta1 from astrocytes almost completely blocked the generation of new neurons in aged transgenic mice. Even young adult TGF-beta1 mice had 60% fewer immature, doublecortin-positive, hippocampal neurons than wild-type littermate controls. Bromodeoxyuridine labeling of dividing cells in 2-month-old TGF-beta1 mice confirmed this decrease in neuro-genesis and revealed a similar decrease in astrogenesis. Treatment of early neural progenitor cells with TGF-beta1 inhibited their proliferation. This strongly suggests that TGF-beta1 directly affects these cells before their differentiation into neurons and astrocytes. Together, these data show that TGF-beta1 is a potent inhibitor of hippocampal neural progenitor cell proliferation in adult mice and suggest that it plays a key role in limiting injury and age-related neurogenesis.