Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD

Background and objective:   Inhaled corticosteroids are used to treat COPD and asthma. An association between sequence variants in the corticotrophin-releasing hormone receptor 1 ( CRHR1 ) gene and improved lung function in asthmatics treated with inhaled corticosteroids was reported recently. This study investigated the association between the change in lung function in response to inhaled corticosteroids and single-nucleotide CRHR1 polymorphisms in patients with COPD.
Methods:   COPD patients ( n  = 87) with a positive smoking history were recruited from the pulmonary clinics of 11 hospitals in Korea. Patients were treated with fluticasone propionate and salmeterol for 12 weeks and lung function was measured at baseline and after the 12-week treatment. Eighty-four of the 87 subjects were successfully genotyped.
Results:   Seventy-one patients with the wild-type GG genotype and 13 patients with the heterozygous GT genotype in rs242 941 were evaluated. After 12-week treatment, the change in FEV₁ was significantly higher in patients with wild-type GG genotype (6.0 ± 0.8% of predicted FEV₁) than in GT heterozygotes (−0.8 ± 1.8, P  = 0.003).
Conclusions:   Improved FEV₁ following inhaled corticosteroid and a long-acting β2-agonist was associated with CRHR1 genetic polymorphism in patients with COPD.     

Reversible encephalopathy following 5-fluorouracil-based chemotherapy in patients with dihydropyrimidine dehyrogenase deficiency

5-fluorouracil (5-FU) is one of the most frequently used chemotherapy agents for the treatment of a number of solid cancers. We report two patients with advanced gastric cancer who developed acute encephalopathy after receiving chemotherapy composed of 5-FU and oxaliplatin. One patient presented with altered consciousness and the other with generalized tonic clonic seizure. 5-FU-induced encephalopathy was suspected by clinical, radiological and electroencephalographic findings, and both patients had reduced expression of dihyropyrimidine dehydrogenase, the rate-limiting enzyme responsible for the catabolism of 5-FU. The neurological symptoms improved spontaneously, and did not recur in the following cycle of chemotherapy with the administration of a reduced dose of 5-FU. We suggest that the early recognition of this adverse event can reverse 5-FU-induced neurological symptoms and a dose reduction of the offending drug can prevent the recurrence of 5-FU induced encephalopathy.     

Prevalence of hypouricaemia and SLC22A12 mutations in healthy Korean subjects

Aim: Mutations in the SLC22A12 gene, which encodes a uric acid transporter, URAT1, are associated with renal hypouricaemia. This study was designed to measure serum uric acid (Sua) levels and allele frequencies of two common mutations in SLC22A12, W258X and R90H, in healthy Korean subjects. Methods: A total of 909 unrelated Korean adults (male : female, 1:1.23; mean age, 48.4 ± 11.0 years) were recruited among those who had taken a routine health check-up in a health centre in 2003. None of them had hypertension, diabetes mellitus, kidney diseases or liver diseases. Genotyping for W258X and R90H was performed using the TaqMan method. Results: The prevalences of hyperuricaemia (Sua levels, >416 µmol/L) and hypouricaemia (Sua levels, <178 µmol/L) were 4.6% and 3.3%, respectively. A marked male preponderance in the hyperuricaemic group was noted, and the men revealed higher Sua than the women. The Sua showed a positive correlation with serum creatinine level and blood pressure. In the hypouricaemic group, the allele frequencies of W258X and R90H were 11.7% and 6.7%, respectively, and the proportion of subjects with one or both of the mutant alleles was 33.3%. Hyperuricaemic subjects never had either mutation. Conclusion: The W258X and/or R90H mutations in the SLC22A12 gene are one of the major factors responsible for hypouricaemia, and one-third of the hypouricaemic subjects had one or both of the mutant alleles.     

Transcatheter arterial chemoembolization vs. chemoinfusion for unresectable hepatocellular carcinoma in patients with major portal vein thrombosis

Background  Transcatheter arterial chemoembolization (TACE) has been limited in palliative treatment of unresectable hepatocellular carcinoma (HCC) with major portal vein (PV) invasion due to the possibility of liver failure following embolization. Transcatheter arterial chemoinfusion (TACI) has been an option in such cases.
Aim  To compare clinical outcomes after TACE vs. TACI in HCC patients with major PV occlusion.
Methods  We compared clinical outcomes after TACE vs. TACI in HCC patients with major PV occlusion. From 2005 to 2007, 110 HCC patients with major PV thrombosis were treated with TACE ( n  = 49) or TACI ( n  = 61).
Results  The morbidity rate was similar for both TACE (6.1%) and TACI (6.5%) patients, and complications were adequately managed using medical treatment. The Kaplan–Meier survival analysis showed that the survival period was significantly longer for the TACE group (median: 14.9 months) than for the TACI (median: 4.4 months) group ( P  < 0.001). There was a higher probability of death in the TACI group than in the TACE group in both our multivariate Cox-proportional hazards (OR 3.09, P  < 0.001) and the propensity score-matched (27 pairs) cohort analyses (OR 2.27, P  = 0.024).
Conclusions  Transcatheter arterial chemoembolization can be safely performed in HCC patients with main PV occlusion. Compared with TACI, TACE may result in longer survival of HCC patients with major PV occlusion.     

Pathological changes according to the severity of asthma

Background There have been many studies concerning pathological changes in bronchial mucosa from asthmatics; however, few studies has been carried out to evaluate pathological changes according to the severity of asthma. Objective This study was designed to evaluate the cellular components in bronchoalveolar lavage fluid (BALF) and histologicai abnormalities in asthmatics according to the severity ot asthma. Methods Bronchoalveolar lavages, bronchoscopic biopsies and ultrastructural examinations were performed in 13 asthmatics and 11 (BAL) or four (biopsies) non-asthmatic controls. The proportions of epithelial cells and eosinophils in BALF were significantly increased in asthmatics and showed significant correlations with PC_20Meth which reflects bronchial hyperresponsiveness. Light microscopic examination revealed loss of epithelium, inllammatory cell infiltrations and thickening of the basement membrane which also showed significant correlation with PC_20Meth. Hypertrophy of airway smooth muscles and hyperplasia of mucous glands were prominent in asthmatics but there was no difference according to the severity of asthma. Ultra-structural examination revealed that basement membrane thickening on light microscopic examination is due to the increased subepithelial collagen deposition with normal thickeness of basal lamina. Conclusion These data suggest that loss of epithelial cells, infiltration of inflammatory cells, especially eosinophils, and increased deposition of subepithelial collagen play major roles in determining the severity of asthma and non-specific bronchial hyperresponsiveness.     

Clinical significance of serum hyaluronic acid as a fibrosis marker in chronic hepatitis C patients treated with interferon-α: Histological evaluation by a modified histological activity index scoring system

Abstract The aim of the present study was to investigate the histological changes effected by interferon (IFN) treatment and to evaluate the clinical significance of serum hyaluronic acid (HA) as a marker of fibrosis. Forty-nine patients with chronic hepatitis C treated with IFN-α were divided into three groups according to the existence of viraemia: sustained complete responders (CR), complete responders with relapse (PR) and non-responders (NR). Needle biopsy sections of the liver taken before and at the end of IFN treatment were assessed according to the modified histological activitindex (HAI) scoring system. Serum fibrosis markers, including HA, were measured at needle biopsies. Biopsies of CR at the end of treatment showed a significant improvement in fibrosis and necroinflammatory scores. More significant correlation was observed between fibrosis scores and serum levels of HA before IFN treatment (r= 0.607, P < 0.0001) than those between fibrosis scores, on the one hand, and pepride of type III procollagen (PIIIP; r= 0.531, P= 0.0004) or type IV collagen 7S domain (type IV-C; r= 0.241, P= 0.1062) on the other. Moreover, serum HA levels fell significantly in patients in whom fibrosis improved (P= 0.011). This is the first paper describing the advantages of the modified HAI scoring system over others in estimating the effect of IFN-α; the results also indicate that serum HA can be useful in monitoring liver fibrosis in chronic hepatitis C patients treated with IFN-α.     

Modulation of the Development of Humoral Immunity by Topically Applied Acetone, Ethanol, and 12-O-Tetradecanoylphorbol-13-Acetate

The effects of topically applied 12-O-tetradecanoylphorbol-13-acetate(TPA), acetone, and ethanol on systemic immune function wereanalyzed in SSIN mice. A total of one, four, or eight dorsalapplications of solvent (50–300 µl/treatment, 2x/week)affected neither the overall cellularity of the spleen nor therelative proportions of splenic cells expressing CD4, CD8, orIg surface markers. In contrast, overall cellularities of thespleen increased and relative T cell content of the spleen decreasedin mice treated multiple times with TPA (2 µg/applicationin 0.2 ml acetone). The development of splenic B cells secretingIgM against sheep red blood cells (SRBC, a T-cell-dependentantigen) was retarded, and the overall duration of IgM synthesiswas decreased, in mice immunized 1 hr after the last of fourapplications (>200 µl) of either solvent. Comparableretardations occurred in mice immunized as late as 7 days aftertermination of solvent treatment. However, solvent effects onthe development of antibody-forming cells were not observedafter eight topical applications or when TNP-LPS (a T cell-independentantigen) was used as the immunogen. The effects of TPA on thedevelopment of IgM-secreting B cells were indistinguishablefrom those of the solvent used for its application. Althoughserum hemagglutination titers to SRBC correlated with the relativenumbers of splenic B cells producing IgM, in vitro proliferativeresponses to B and T cell mitogens were not predictive of theeffects of solvents or TPA on the development of antibodysecretingcells. Collectively, these studies demonstrate that topicallyapplied acetone and ethanol can systemically modulate humoralimmunity and emphasize the need for inclusion of nontreatedcontrols when assessing the potential immunomodulatory activitiesof agents dissolved in acetone or ethanol.     

A monoclonal antibody recognizing a determinant shared by HLA-A2 and HLA-Aw69 (A28* variant)

A cytotoxic murine monoclonal antibody, designated P5.1, was tested against 613 unrelated donors and found to react with 401 who were positive for HLA-A2 (sensitivity = 100%) and with 8 of 82 positive for HLA-A28. The latter split of A28 corresponds to the "A28* variant" that in the Ninth International Histocompatibility Workshop (9WS) was designated Aw69(28*). The epitope recognized by antibody P5.1 is distinct from the alloantisera-defined determinants that characterize HLA-A2 and A28. Immunoprecipitation of specific antigens with selected monoclonal antibodies and isoelectric focusing gel electrophoresis demonstrated that A2, Aw68(28) and Aw69(28*) are distinct polypeptides. Thus, the A2-A28 antigen family consists of at least three different alleles definable using alloantiserums specific for A2 and A28, and monoclonal antibodies such as P5.1 recognizing the A2,Aw-69(28*)-epitope.