The addition of adefovir dipivoxil (ADV) to ongoing lamivudine therapy is effective against lamivudine-resistant virus in patients with hepatitis B virus (HBV) infection. We studied 39 patients who received ADV added to lamivudine for breakthrough hepatitis. We determined early viral changes (12 weeks) in YMDD mutants (rtM204I [YIDD sequence], rtM204V [YVDD]) and rtL180M in all 39 patients as well as amino acid changes in the polymerase reverse transcriptase (rt) region and precore/core promoter mutations in 15 patients who received long-term treatment (more than 1 year). Changes in rtM204I and rtL180M viral loads were greater than that of the rtM204V, albeit statistically insignificant. Moreover, the greatest change in viral load was seen for rtM204I without hepatitis B e antigen (HBeAg). The precore mutant was replaced with wild-type virus in three of eight patients after 1 year of added ADV therapy. Compared to baseline with lamivudine therapy only, new amino acid mutations were seen in the rt region at baseline with ADV in seven patients. At 1 year after ADV coadministration, the YMDD motif was replaced with wild-type (rt204M) in two patients, in whom mutations were fewer and of a different type. We conclude that the rtM204I may be more sensitive to ADV in vivo. ADV tended to select wild-type virus from precore mutants. Moreover, viruses that were wild-type in the rt region reappeared after 1 year of ADV coadministration in some patients.

Adenine↗

PubMed2006

Recommended initial loading dose of teicoplanin, established by therapeutic drug monitoring, and outcome in terms of optimal trough level.

Teicoplanin has a long serum half-life, and therefore it takes time to reach a steady-state concentration. An initial loading procedure has been recommended for teicoplanin to enable prompt reaching of the optimal serum trough level (10-15 microg/ml). However, the dose of teicoplanin that should be administered to patients with varying renal function levels remains inconclusive. In this study, we monitored the serum concentrations of teicoplanin in patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and compared different teicoplanin serum concentrations and their clinical efficacy, investigating the significance of the mean dose administered during the initial 3 days. The study included 48 patients with MRSA pneumonia. The peak and trough concentrations of teicoplanin were determined utilizing a fluorescence polarization immunoassay and a two-compartment Bayesian population model. Teicoplanin was given at a loading dose of 400 or 800 mg on the first day, followed by maintenance doses of 200 or 400 mg. The mean initial dose (MID) over the first 3 days was calculated as: (loading dose + dose on 2nd day + dose on 3rd day)/3. Patients with an MID of 266.7 mg or less (400 mg for loading, 200 mg over the 2nd and 3rd days) did not have a trough level that exceeded 10 microg/ml at the point before the injection on the 4th day. Even in patients with hemodialysis (HD), an MID of 266.7 mg was not enough to provide a trough level of 10 microg/ml. Patients with an MID than 533.3 mg had significantly elevated trough levels, showing better outcomes. A multiple regression formula for predicting trough level before the fourth day of administration is given as: 0.034 + 0.030 x (MID; mg) - 0.057 x creatinine clearance (Ccr; ml/min). These findings suggest that 800 mg as an initial dose, followed by 400 mg maintenance doses over the following 2 days, makes it possible to safely attain an optimal trough level, even in the patients with HD.

Aged↗

PubMed2006

A validation and potential modification of the pneumonia severity index in elderly patients with community-acquired pneumonia.

OBJECTIVES: To evaluate the discriminatory power of the Pneumonia Severity Index (PSI) in elderly patients with community-acquired pneumonia (CAP) and to improve its performance. DESIGN: Retrospective review of 193 patients from 1999 to 2001 to derive prognostic rules. The rules were prospectively validated in 144 patients from 2002 to 2003. SETTING: Iwata City Hospital, a 400-bed general hospital. PARTICIPANTS: Patients aged 80 and older who had CAP and were admitted to the hospital. MEASUREMENTS: Predictors of 30-day mortality were identified using logistic regression analysis, and several rules were constructed by combining the PSI and the independent predictors. RESULTS: The original PSI, which defines PSI Class IV and V as a high-risk group, did not perform well in discriminating survivors from nonsurvivors (sensitivity 100%, specificity 15%), whereas a modified PSI, which defines only PSI Class V as a high-risk group, performed better (sensitivity 86%, specificity 63%). Three predictors for mortality were identified independent from the modified PSI: performance status (PS) Grade 3 or higher, anorexia, and partial pressure of carbon dioxide of 50 mmHg or greater. By combining the modified PSI and PS, the performance could be further improved (sensitivity 79%, specificity 80%). CONCLUSION: The modified PSI could identify low-risk patients more accurately than the original PSI. In addition, by combining the modified PSI with PS, higher performance was obtained. Such information would aid physicians in clinical decision-making without overestimating the risk for elderly patients with CAP.

Aged, 80 and over↗

PubMed2006

1,25-dihydroxyvitamin D3 and its receptor inhibit the chenodeoxycholic acid-dependent transactivation by farnesoid X receptor.

Farnesoid X receptor (FXR), the receptor for bile acids, including chenodeoxycholic acid (CDCA), is a member of the nuclear receptor superfamily, which also includes the receptors for retinoic acid, vitamin D (D3), thyroid hormone, thiazolidinedione and 22(R)-hydroxycholesterol. Here, we have evaluated the effects of a series of ligands and their receptors on the promoter activity induced by CDCA/FXR. The kidney cell line, CV1, was cotransfected with FXR-expression plasmid and the luciferase-based reporter gene that has a thymidine kinase promoter fused to the canonical FXR-responsive element or the natural promoter for the small heterodimer partner (SHP), bile salt export pump (BSEP), and ileum bile acid (I-BABP) gene. D3 and its receptor (VDR) inhibited the transactivation of all four reporter constructs that are enhanced by CDCA/FXR. The effect of D3 on the expression of the BSEP and SHP genes in HepG2 cells and that of the I-BABP gene in Caco-2 cells were confirmed by reverse transcription (RT)-PCR. Deletion analysis of VDR revealed that its ligand-binding domain (LBD) is responsible for the repression and the DNA-binding domain (DBD) is dispensable. Specific interaction between FXR and VDR was detected with the in vitro pull-down assay using chimeric FXR or VDR fused to glutathione-S-transferase.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

[Guideline for the treatment of Graves' disease with antithyroid drug].

We have published "Guideline for the Treatment of Graves' Disease with Antithyroid Drug in Japan 2006" in the middle of May from the Japan Thyroid Association. The background, working process, composition, aim and significance of this guideline are described. The most remarkable feature of this guideline is "evidence based".

Antithyroid Agents↗

PubMed2006

[Method of medical treatment for Graves' disease based on evidence based medicine].

The Japan Thyroid Association has recently published the guideline for the treatment of Graves' disease with antithyroid drugs (ATD). According this guideline, "the best method of medical treatment for Graves' disease" is described here. The topics in this article include the following: the selection of ATD (Which is better, methimazole or propylthiouracil?), the suitable starting dosage of ATD (Is methimazole 15 mg daily equally effective as 30 mg daily?), the way of decreasing ATD (Is the titlation method to decrease the dosage of ATD suitable?), the duration of the ATD treatment (How long should the ATD treatment be continued?), the relation to smoking (Should smoking be prohibited for patients with Graves' disease?) and the restriction of iodine (Should patients restrict dietary iodine intake?).

Antithyroid Agents↗

PubMed2006

[Thyroid hormones and lipid metabolism].

Thyroid hormone (T3) and its receptor (TR) have the diverse effects on the lipid metabolism and hypothyroidism causes hypercholesterolaemia characterized by increased levels of low-density ripoproteins (LDL). There are multiple TR isoforms such as TRalpha1, TRbeta1 and TRbeta2, of which expressions are known to be tissue-specific. For example, TRbeta1 is the major TR in the liver while T3 action is mediated via TRalpha1 in the heart. The X-ray crystallography of the ligand-binding domain of TRs enabled the development of TRbeta isoform specific T3 analogues including GC1. Without tachycardia, GC1 selectively targets the TRbeta1 in the liver and decreases cholesterol levels with more potent efficacy than that of atorvastatin, a potent HMG-CoA reductase. However, the reduction of serum TSH by GC1 should be overcome in future. Current reports also describe the existence of the complex cross-talks in the lipid metabolism between TR and other nuclear hormone receptors including peroxisome proliferator -activated receptors (PPARs), liver X receptor alpha (LXRalpha) and farnesoid X receptors (FXRs). Understanding for the function of TRs and other nuclear factors may provide the new approach to the control of hypercholesterolaemia.

Animals↗

PubMed2005

Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner.

Mdm2 promotes ubiquitination of the tumor suppressor p53 and can function as an oncogene by largely downregulating p53. Although a p53-independent role of Mdm2 has been reported, the underlying mechanism remains unclear. In the present study, we indicated that Mdm2 is involved in p53-independent carcinogenesis via downregulation of pRB. Expression of pRB showed an apparent inverse correlation with Mdm2 expression in 30 patients with non-small cell lung cancer. There were some cases with the p53 mutations in which a high level of Mdm2 and a low level of pRB were expressed. Mdm2 promoted ubiquitination of pRB in cells without wild-type p53. Furthermore, pRB-mediated G1 arrest in a p53-deficient cell line, SRB1, was significantly enhanced by a mutant Mdm2 that lacks pRB ubiquitination activity. Soft-agar colony formation activity of p53-knockout MEF was increased by wild-type Mdm2 but not mutant Mdm2. These findings suggest that overexpression of Mdm2 can perturb a RB pathway regardless of the p53 gene status, promoting carcinogenesis.

Adenovirus E1A Proteins↗

PubMed2005

Immunization with dendritic cells retrovirally transduced with mycobacterial antigen 85A gene elicits the specific cellular immunity including cytotoxic T-lymphocyte activity specific to an epitope on antigen 85A.

In the present study, we evaluated antigen 85A (Ag85A) gene-transduced dendritic cells (DCs) vaccine against Mycobacterium tuberculosis. Murine bone marrow-derived DCs were retrovirally transduced with mycobacterial Ag85A gene and injected to BALB/c mice intravenously. The DC vaccine was capable of inducing purified protein derivative (PPD)- and the antigen-specific spleen cell proliferation and IFN-gamma production from both CD4+ and CD8+ T cells in spleens of the immune mice. In addition, the DC vaccination induced cytotoxic T-lymphocytes (CTL) and IFN-gamma-producing cells specific for a 9-mer CTL epitope on Ag85A molecule. This eliciting cellular immunity led to protection against wasting disease due to M. tuberculosis infection and induction of moderate bacterial clearance.

Animals↗

PubMed2005

[Fournier's gangrene with diabetes mellitus].

Explore the source record for details and available documents.

Adult↗

PubMed2005

alpha-Galactosylceramide, a ligand of natural killer T cells, inhibits allergic airway inflammation.

alpha-Galactosylceramide (alpha-GalCer) is a specific ligand of natural killer T cells (NKT cells) that regulates the immune responses such as tumor rejection and autoimmunity by producing interferon (IFN)-gamma and interleukin (IL)-4. However, it has not been determined whether alpha-GalCer-activated NKT cells modulate allergic inflammation. Because alpha-GalCer induces a large amount of IFN-gamma production by NKT cells, we hypothesized that an in vivo administration of alpha-GalCer could inhibit allergic airway inflammation in mice. Strikingly, a single intraperitoneal injection of alpha-GalCer almost completely abrogated an infiltrate with eosinophils in the lung tissue as well as in the bronchoalveolar lavage. This inhibition of allergic inflammation was associated with a significant decrease in the levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and in the number of goblet cells. In addition, this ligand significantly inhibited airway hyperresponsiveness to inhaled methacholine and raised the serum levels of ovalbumin-specific IgG2a with a decrease in those of ovalbumin-specific IgE. In IFN-gamma knockout mice, however, alpha-GalCer failed to exert such inhibitory effects in this asthma model. These results indicate that alpha-GalCer prevents allergic airway inflammation possibly through IFN-gamma production by ligand-activated NKT cells, suggesting the potential therapeutic application of alpha-GalCer in asthma.

Animals↗

PubMed2005

Impaired toll-like receptor 9 expression in alveolar macrophages with no sensitivity to CpG DNA.

Unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (ODN) potently stimulate the innate immune system, and they are recognized by Toll-like receptor 9 (TLR9), which is expressed by monocytes/macrophages, dendritic cells, and B cells. However, it is unknown whether alveolar macrophages (AMs) express functional TLR9. To clarify this, we analyzed mRNA expressions of TLRs in murine AMs by real-time polymerase chain reaction, and compared with those in other tissue macrophages and lung antigen-presenting cells. In addition, we determined the sensitivity of these cell populations to CpG-ODN. Interestingly, TLR9 mRNA was almost absent in AMs, but highly expressed in bone marrow-derived macrophages and peritoneal macrophages, whereas TLR2 and TLR4 were present in all macrophage populations. Consistent with the receptor expression, AMs showed no sensitivity to CpG-ODN, whereas other macrophage populations secreted tumor necrosis factor alpha, interleukin 12 p40, and interleukin 6, and enhanced expression of CD40, CD80, and CD86, in response to CpG-ODN. Lung dendritic cells and B cells highly expressed TLR9 mRNA and responded to CpG-ODN. These results indicate selective loss of TLR9 expression in AMs with no sensitivity to CpG-ODN, suggesting that dendritic cells and B cells play a role in the immune response against bacterial DNA in the lung.

Analysis of Variance↗

PubMed2005

Differences in clinical features and prognosis of interstitial lung diseases between polymyositis and dermatomyositis.

OBJECTIVE: To assess the difference in clinical features and prognosis of patients with interstitial lung disease (ILD) comparing polymyositis (PM) and dermatomyositis (DM). METHODS: Medical records of 28 ILD patients with PM/DM (16 PM-ILD, 12 DM-ILD) were reviewed retrospectively. RESULTS: Serum CPK concentrations were significantly higher in PM-ILD than in DM-ILD. Bronchoalveolar lavage analysis showed that the percentages of lymphocytes and eosinophils were significantly higher in DM-ILD than in PM-ILD. Ten patients (5 PM-ILD, 5 DM-ILD) underwent surgical lung biopsy, and 3 (3 DM-ILD) had an autopsy. Nonspecific interstitial pneumonia (NSIP) was found in 7 (4 PM-ILD, 3 DM-ILD) and usual interstitial pneumonia (UIP) in 3 (1 PM-ILD, 2 DM-ILD). Interestingly, diffuse alveolar damage (DAD) was found in 3 patients with DM-ILD, who all died of deterioration of ILD; but no one with PM-ILD had DAD. Corticosteroid treatment alone achieved a favorable response in 6 patients (37.5%) with PM-ILD, but in only one (8.3%) with DM-ILD. Administration of cyclosporine in the early phase of onset benefited 4 corticosteroid-resistant patients with DM-ILD. Conclusively, survival in DM-ILD was significantly worse than that in PM-ILD. CONCLUSION: DM-ILD is more refractory to corticosteroid therapy, resulting in poorer prognosis compared with PM-ILD. These data indicate that intensive therapy, including cyclosporine, should be considered for DM-ILD.

Bronchoalveolar Lavage Fluid↗