The feasibility of discontinuing lamivudine in lamivudine-resistant chronic hepatitis B patients on lamivudine and adefovir combination therapy.

OBJECTIVES: This study investigated the antiviral efficacy of adefovir (ADV) rescue therapy and the feasibility of lamivudine (LAM) discontinuation in LAM-resistant chronic hepatitis B (CH-B) patients who had attained a virological response (VR) with LAM + ADV combination therapy. METHODS: The VR and virological breakthrough (VBT) were analyzed in 106 consecutively enrolled LAM-resistant CH-B patients who received ADV rescue therapy during a mean follow-up period of 55.2 months. Seventy-four patients achieved VR, and were divided into the LAM-discontinuation group (n = 39) and the LAM-continuation group (n = 35). The VR and VBT between the 2 groups were compared. RESULTS: For all 106 LAM-resistant CH-B patients, the overall cumulative probabilities of VR at 1, 2, 3 and 5 years of ADV rescue therapy were 40.6, 55.7, 64.6 and 81.3%, respectively. The cumulative probabilities of VBT at 1, 2, 3 and 5 years were 0, 2.9, 8.8 and 13.9%, respectively. Whether they discontinued or continued LAM after achieving VR on LAM + ADV therapy, VR and VBT were not significantly different during a mean follow-up period of 40.4 months. CONCLUSIONS: There was a good long-term VR with ADV rescue therapy for LAM-resistant CH-B patients. Moreover, discontinuing LAM was found to be feasible for patients who attained VR during ADV + LAM therapy.

PHACE association with intracranial, oropharyngeal hemangiomas, and an atypical patent ductus arteriosus arising from the tortuous left subclavian artery in a premature infant.

PHACE association is a rare neurocutaneous condition in which facial hemangiomas associate with a spectrum of posterior fossa malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, and eye anomalies. We reported a case of PHACE association in a premature infant showing facial, intracranial, and oropharyngeal hemangiomas with evidence of the Dandy-Walker variant and complicated cardiovascular anomalies, including a right-sided aortic arch and an atypical patent ductus arteriosus arising from a tortuous left subclavian artery. To our knowledge, intracranial hemangiomas are rare in PHACE association, and a concomitant oropharyngeal hemangioma has not been previously reported in the PHACE association literature. In infants presenting with large, plaque-like facial hemangiomas, it is important to conduct active cardiovascular and neurological evaluations. Special attention should be given to the laryngoscopic examination to search for additional hemangiomas in the airway.

Coinfection of hepatitis A virus genotype IA and IIIA complicated with autoimmune hemolytic anemia, prolonged cholestasis, and false-positive immunoglobulin M anti-hepatitis E virus: a case report.

A 37-year-old male presented with fever and jaundice was diagnosed as hepatitis A complicated with progressive cholestasis and severe autoimmune hemolytic anemia. He was treated with high-dose prednisolone (1.5 mg/kg), and eventually recovered. His initial serum contained genotype IA hepatitis A virus (HAV), which was subsequently replaced by genotype IIIA HAV. Moreover, at the time of development of hemolytic anemia, he became positive for immunoglobulin M (IgM) anti-hepatitis E virus (HEV). We detected HAV antigens in the liver biopsy specimen, while we detected neither HEV antigen in the liver nor HEV RNA in his serum. This is the first report of hepatitis A coinfected with two different genotypes manifesting with autoimmune hemolytic anemia, prolonged cholestasis, and false-positive IgM anti-HEV.

[Comparison between conventional 4 L polyethylene glycol and combination of 2 L polyethylene glycol and sodium phosphate solution as colonoscopy preparation].

BACKGROUND/AIMS: Effective bowel preparation is essential for accurate diagnosis of colon disease. We investigated efficacy and safety of 2 L polyethylene glycol (PEG) solution with 90 mL sodium phosphate (NaP) solution compared with 4 L PEG method. METHODS: Between August 2009 and April 2010, 526 patients were enrolled who visited Seoul National University Bundang Hospital for colonoscopy. We allocated 249 patients to PEG 4 L group and 277 patients to PEG 2 L with NaP 90 mL group. Detailed questionnaires were performed to investigate compliance, satisfaction and preference of each method. Bowel preparation quality and segmental quality were evaluated. Success was defined as cecal intubation time less than 20 minutes without any help of supervisors. RESULTS: Both groups revealed almost the same baseline characteristics except the experience of operation. PEG 4 L group's compliance was lower than PEG 2 L with NaP 90 mL group. Success rate and cecal intubation time was not different between two groups. Overall bowel preparation quality of PEG 2 L with NaP 90 mL group was better than PEG 4 L group. Segmental bowel preparation quality of PEG 2 L with NaP 90 mL group was also better than PEG 4 L group in all segments, especially right side colon. Occurrence of hyperphosphatemia was higher in PEG 2 L with NaP 90 mL group than PEG 4 L group. However, significant adverse event was not reported. CONCLUSIONS: PEG 2 L with NaP 90 mL method seems to be more effective bowel preparation than PEG 4 L method.

[Efficacy and predictors of the virologic response to entecavir therapy in nucleoside-naive patients with chronic hepatitis B].

BACKGROUND/AIMS: The aim of this study was to elucidate the antiviral efficacy and the predictors of entecavir treatment in nucleoside-naive chronic hepatitis B patients. METHODS: A total of 160 patients treated with entecavir (0.5 mg daily) for at least 24 weeks were consecutively enrolled. The virologic response (HBV DNA<2,000 copies/mL), biochemical response (ALT< or = upper limit of normal), and virologic breakthrough (>1 log(10) copies/mL increase in HBV DNA level above nadir on two consecutive occasions) were retrospectively analyzed. RESULTS: The mean follow-up duration was 58.8 weeks, and 85 patients (53.1%) showed HBeAg positivity. The median pretreatment levels of serum ALT and HBV DNA were 99 IU/L and 7.6 log(10) copies/mL, respectively. The cumulative rates at 12, 24, 48, and 72 weeks were 37.5%, 68.1%, 87.4%, and 95.8%, respectively, for the virologic response; 40.0%, 66.2%, 84.5%, and 92.7% for the biochemical response; 10.6%, 18.8%, 27.0%, and 34.5% for HBeAg loss; and 3.5%, 7.1%, 9.0%, and 13.2% for HBeAg seroconversion. There was no case of virologic breakthrough. An absence of HBeAg and a low serum HBV DNA level (<8 log(10) copies/mL) at baseline were significant predictors of the virologic response in a multivariate analysis (P<0.01). CONCLUSIONS: Entecavir therapy showed excellent efficacy in nucleoside-naive chronic hepatitis B patients. The predictors of a virologic response were an absence of HBeAg and a low baseline HBV DNA level.

Sorafenib-induced interstitial pneumonitis in a patient with hepatocellular carcinoma: a case report.

Sorafenib is an oral multikinase inhibitor that has shown a survival benefit in patients with advanced hepatocellular carcinoma, and is considered to be generally safe. We treated a patient with interstitial lung disease that was associated with sorafenib therapy for the treatment of advanced hepatocellular carcinoma. A 74-year-old man with hepatitis-C-virus-related hepatocellular carcinoma was treated with sorafenib. After 8 days of sorafenib administration, he received radiation therapy for an intrahepatic tumor located in segment eight. On the 24th day of sorafenib treatment, the patient developed acute interstitial pneumonitis that rapidly improved after the discontinuation of sorafenib and treatment with high-dose steroids. This case alerts physicians to the possibility of sorafenib-induced interstitial lung disease.

Functional genomics of innate host defense molecules in normal human monocytes in response to Aspergillus fumigatus.

Aspergillus fumigatus induces the release of innate immune-related molecules from phagocytic cells early in the course of infection. Little is known, however, about the complex expression profiles of the multiple genes involved in this response. We therefore investigated the kinetics of early gene expression in human monocytes (HMCs) infected with conidia of A. fumigatus using DNA microarray analysis. Total RNA from HMCs at 0, 2, 4, and 6 h was extracted, linearly amplified, hybridized onto Affymetrix HG133 Plus 2.0 gene chips, and analyzed with an Affymetrix scanner. Changes in gene expression were calculated as a ratio of those expressed by infected versus control HMCs. Aspergillus fumigatus induced differential regulation of expression in 1,827 genes (P < 0.05). Genes encoding cytokines and chemokines involved in host defense against A. fumigatus, including interleukin-1beta (IL-1beta), IL-8, CXCL2, CCL4, CCL3, and CCL20, as well as the opsonin long pentraxin 3, were up-regulated during the first 2 to 6 h, coinciding with an increase in phagocytosis. Simultaneously, genes encoding CD14, ficolin1, and MARCO were down-regulated, and genes encoding IL-10 and matrix metalloproteinase 1 were up-regulated. Up-regulation of the genes encoding heat shock proteins 40 and 110 and connexins 26 and 30 may point to novel molecules whose role in the pathogenesis of aspergillosis has not been previously reported. Verification of the transcriptional profiling was obtained for selected genes by reverse transcription-PCR and enzyme immunoassay. Thus, A. fumigatus conidia induced a coordinated expression of genes important in host defense and immunomodulation.

Use of quantitative real-time PCR to study the kinetics of extracellular DNA released from Candida albicans, with implications for diagnosis of invasive Candidiasis.

Quantitative real-time PCR (qPCR) is considered one of the most sensitive methods to detect low levels of DNA from pathogens in clinical samples. To improve the design of qPCR for the detection of deeply invasive candidiasis, we sought to develop a more comprehensive understanding of the kinetics of DNA released from Candida albicans in vitro and in vivo. We developed a C. albicans-specific assay targeting the rRNA gene complex and studied the kinetics of DNA released from C. albicans alone, in the presence of human blood monocytes (H-MNCs), and in the bloodstream of rabbits with experimental disseminated candidiasis. The analytical qPCR assay was highly specific and sensitive (10 fg). Cells of C. albicans incubated in Hanks balanced salt solution (+/-10% bovine serum albumin [BSA]) or RPMI (+/-10% BSA) showed a significant release of DNA at T equal to 24 h compared to T equal to 0 h (P < or = 0.01). C. albicans incubated with H-MNCs exhibited a greater release of DNA than C. albicans cells alone over 24 h (P = 0.0001). Rabbits with disseminated candidiasis showed a steady increase of detectable DNA levels in plasma as disease progressed. Plasma cultures showed minimal growth of C. albicans, demonstrating that DNA extracted from plasma reflected fungal cell-free DNA. In summary, these studies of the kinetics of DNA release by C. albicans collectively demonstrate that cell-free fungal DNA is released into the bloodstream of hosts with disseminated candidiasis, that phagocytic cells may play an active role in increasing this release over time, and that plasma is a suitable blood fraction for the detection of C. albicans DNA.

Genetic heterogeneity of the hexon gene of adenovirus type 3 over a 9-year period in Korea.

Hexon sequences were analyzed in 29 epidemiologically unrelated adenovirus type 3 (Ad3) isolates from the 7 genome types to understand the molecular basis of the genome-type diversity of Ad3 associated with childhood pneumonia in Korea during the period 1991-1999. Nine nucleotide substitutions were observed among the 29 Ad3 strains. Five of the 9 involved amino acid changes in loops 1 (Gly to Val at codon 205 and Thr to Ile at 211) and loop 2 (His to Asn at 417, Thr to Ala at 429, and Ala to Asp at 439). The predicted hydropathic characteristics of this region have been affected by these amino acid changes. The region surrounding codons from 417 to 439 of Ad3a16 and Ad3a18 manifested greater hydrophobicity than the region of other genome types (Ad3a, Ad3a13, Ad3a14, Ad3a15, and Ad3a17). In particular, three amino acid changes in loop 2 were associated with two new genome types, namely, Ad3a16 and Ad3a18, which were recognized during later epidemics in 1998-1999. Phylogenetic relatedness revealed that these two genome types clustered into distinct lineages in the phylogenetic tree. This result suggests that the genetic heterogeneity of Ad3 hexon could play a potential role in the appearance of new genome types and that it could affect the antigenic characteristics of Ad3.

Adenovirus type 7 peptide diversity during outbreak, Korea, 1995-2000.

To understand the molecular basis of observed regional shifts in the genome types of adenovirus type 7 (Ad7) isolated in Korea during nationwide outbreaks from 1995 to 2000, the genetic variabilities of Ad7d and Ad7l were studied by sequence analysis of hexon, fiber, E3, and E4 open reading frame (ORF) 6/7 peptides. One amino acid change in the receptor-binding domain of fiber and 6 amino acid variations in E4 ORF 6/7 were identified between 2 genome types, while no variations were found in hexon and E3. Phylogenetic trees based on hexon, fiber, and E4 suggested that the Ad7 epidemic was probably caused by the introduction of the Japanese Ad7d strains. Our data also provide evidence that the rapid divergence of Ad7d to a novel genome type Ad7l could have been due to viral strategies involving multiple sequence changes in E4. This result suggests fiber and E4 ORF 6/7 peptides participate in the evolution of Ad7.

Expression of genes encoding innate host defense molecules in normal human monocytes in response to Candida albicans.

Little is known about the regulation and coordinated expression of genes involved in the innate host response to Candida albicans. We therefore examined the kinetic profile of gene expression of innate host defense molecules in normal human monocytes infected with C. albicans using microarray technology. Freshly isolated peripheral blood monocytes from five healthy donors were incubated with C. albicans for 0 to 18 h in parallel with time-matched uninfected control cells. RNA from monocytes was extracted and amplified for microarray analysis, using a 42,421-gene cDNA chip. Expression of genes encoding proinflammatory cytokines, including tumor necrosis factor alpha, interleukin 1 (IL-1), IL-6, and leukemia inhibitory factor, was markedly enhanced during the first 6 h and coincided with an increase in phagocytosis. Expression of these genes returned to near baseline by 18 h. Genes encoding chemokines, including IL-8; macrophage inflammatory proteins 1, 3, and 4; and monocyte chemoattractant protein 1, also were strongly up-regulated, with peak expression at 4 to 6 h, as were genes encoding chemokine receptors CCR1, CCR5, CCR7, and CXCR5. Expression of genes whose products may protect monocyte viability, such as BCL2-related protein, metallothioneins, CD71, and SOCS3, was up-regulated at 4 to 6 h and remained elevated throughout the 18-h time course. On the other hand, expression of genes encoding T-cell-regulatory molecules (e.g., IL-12, gamma interferon, and transforming growth factor beta) was not significantly affected during the 18-h incubation. Moreover, genes encoding IL-15, the IL-13 receptor (IL-13Ra1), and CD14 were suppressed during the 18-h exposure to C. albicans. Thus, C. albicans is a potent inducer of a dynamic cascade of expression of genes whose products are related to the recruitment, activation, and protection of neutrophils and monocytes.