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Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL‐1. Here, we present results from the similar EPCORE NHL‐3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20+ B‐cell non‐Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28‐day cycles; once weekly during cycles 1–3, every 2 weeks during cycles 4–9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step‐up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow‐up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut‐off. The most common treatment‐emergent adverse events of any grade were CRS (83.3%), injection‐site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1–2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines. [ABSTRACT FROM AUTHOR]

Summary: Dysbiosis of the gut microbiota has been reported to increase early complications after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). However, it remains unclear whether gut microbial alterations persist during late complications, such as chronic graft‐versus‐host disease (cGVHD) or secondary cancers. Here, we analysed the gut microbiota of 59 patients who survived for 1–21.7 years (median, 6.4 years) after allo‐HSCT. Long‐term survivors showed lower gut microbial diversity than the age‐ and sex‐matched healthy controls. This decreased diversity was reflected in the reduced abundance of the butyrate‐producing bacteria. Patients with a history of grade 3 acute graft‐versus‐host disease (aGVHD) exhibited higher Veillonella abundance than patients with a history of grade 1–2 or non‐aGVHD cases. The abundance of Faecalibacterium showed no decrease only in limited cGVHD cases. Additionally, the microbial structure in the secondary cancer group was significantly different (p < 0.05) from that in the non‐secondary cancer group. This study is the first to show that microbial dysbiosis is present over a 10‐year lifetime after discharge following allo‐HSCT. Our results suggest that these prolonged gut microbial alterations may be associated with the development and exacerbation of late complications in post‐transplant survivors. [ABSTRACT FROM AUTHOR]

DSP‐7888 is an immunotherapeutic cancer vaccine derived from the Wilms' tumor gene 1 (WT1) protein. This phase 1/2 open‐label study evaluated the safety and efficacy of DSP‐7888 dosing emulsion in patients with myelodysplastic syndromes (MDS). DSP‐7888 was administered intradermally (3.5 or 10.5 mg) every 2 weeks for 6 months and then every 2‐4 weeks until lack of benefit. Twelve patients were treated in phase 1 (3.5 mg, n = 6; 10.5 mg, n = 6), with no dose‐limiting toxicities reported. Thus, the 10.5 mg dose was selected as the recommended phase 2 dose, and 35 patients were treated in phase 2. Forty‐seven patients received ≥1 dose of the study drug and comprised the safety analysis set. The most common adverse drug reaction (ADR) was injection site reactions (ISR; 91.5%). Grade 3 ISR were common (58.8%) in phase 1 but occurred less frequently in 2 (22.9%) following implementation of risk minimization strategies. Other common ADR were pyrexia (10.6%) and febrile neutropenia (8.5%). In the efficacy analysis set, comprising patients with higher‐risk MDS after azacitidine failure in phases 1 and 2 (n = 42), the disease control rate was 19.0%, and the median overall survival (OS) was 8.6 (90% confidence interval [CI], 6.8‐10.3) months. Median OS was 10.0 (90% CI, 7.6‐11.4) months in patients with a WT1‐specific immune response (IR; n = 33) versus 4.1 (90% CI, 2.3‐8.1) months in those without a WT1‐specific IR (n = 9; P =.0034). The acceptable safety and clinical activity findings observed support the continued development of DSP‐7888 dosing emulsion. [ABSTRACT FROM AUTHOR]

FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD) mutation‐positive acute myeloid leukemia (AML) has a poor prognosis. We report the first case of successful bridge therapy of novel FLT3 inhibitor, quizartinib, to umbilical cord blood stem cell transplantation for FLT3‐ITD‐positive AML‐primary induction failure patients with central nervous system involvement. [ABSTRACT FROM AUTHOR]

E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin‐2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single‐arm phase II study of E7777 in patients with relapsed or refractory peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T‐cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression‐free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment. [ABSTRACT FROM AUTHOR]

Pemetrexed has significant efficacy for some non‐squamous non‐small cell lung cancer cases, as demonstrated in the current case. For those patients, pemetrexed administration should be carefully considered. [ABSTRACT FROM AUTHOR]

Hypertrophic pulmonary osteoarthropathy (HPOA) is a rare paraneoplastic syndrome. Our literature review shows the location of arthralgia and existence of edema are referable information for the differential diagnosis in paraneoplastic arthralgia. [ABSTRACT FROM AUTHOR]

Asymptomatic pulmonary sarcoidosis can develop after starting antiretroviral therapy. The decision on whether to treat sarcoidosis with corticosteroids should be based on the disease severity. [ABSTRACT FROM AUTHOR]

We believe that our report and further case reports on T‐cell chronic lymphocytic leukemia with genetic profile will contribute to the molecular classification of this rare but distinct disease. [ABSTRACT FROM AUTHOR]

Summary: The human gut harbours diverse microorganisms, and gut dysbiosis has recently attracted attention because of its possible involvement in various diseases. In particular, the lack of diversity in the gut microbiota has been associated with complications of haematopoietic stem cell transplantation (HSCT), such as infections, acute graft‐versus‐host disease and relapse of primary disease, which lead to a poor prognosis. However, few studies have serially examined the composition of the intestinal microbiota after HSCT. In this study, we demonstrated, using next‐generation sequencing of the bacterial 16S ribosomal RNA gene, combined with uniFrac distance analysis, that the intestinal microbiota of patients undergoing allogeneic HSCT substantially differed from that of healthy controls and recipients of autologous transplants. Faecal samples were obtained daily throughout the clinical course, before and after transplantation. Notably, the proportions of Bifidobacterium and genera categorized as butyrate‐producing bacteria were significantly lower in patients with allogeneic HSCT than in healthy controls. Furthermore, among allogeneic transplant recipients, a subgroup with a preserved microbiota composition showed a benign course, whereas patients with a skewed microbiota showed a high frequency of complications and mortality after transplantation. Thus, we conclude that the stability of intestinal microbiota is critically involved in outcomes of HSCT. [ABSTRACT FROM AUTHOR]

Serum KL-6 can distinguish between different phenotypes of severe COVID-19 We read the article by D'Alessandro et al with great interest and appreciate their efforts to evaluate the role of serum Krebs von den Lungen-6 (KL-6) as a prognostic biomarker of severe coronavirus disease 2019 (COVID-19).1 KL-6 is a mucin-like high-molecular-weight glycoprotein expressed in type II pneumocytes and respiratory bronchiolar epithelial cells in the healthy lung.2 Elevated serum levels can predict the prognosis of various interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF),3 and D'Alessandro et al1 observed a significant increase in serum KL-6 in critically ill patients with COVID-19 who required mechanical ventilation or intensive care. Here, we report different serum KL-6 kinetics in two patients with severe COVID-19. [Extracted from the article]

Digital clubbing usually occurs bilaterally; however, unilateral clubbing can be seen in hemiplegia and local vascular lesions. We highlight a case of unilateral digital clubbing due to putaminal hemorrhage. Further accumulation of cases will enable exploration of the mechanisms of clubbing. [ABSTRACT FROM AUTHOR]

Although many reports have already shown RSV outbreaks among hemato-oncology patients, genomic studies detecting similar RSV strains prior to an outbreak in the hospital are rare. In 2014, the University of the Ryukyus hospital hemato-oncology unit experienced, and successfully managed, a respiratory syncytial virus (RSV) nosocomial outbreak. During the outbreak investigation, genotyping and phylogenetic analysis was used to identify a potential source for the outbreak. Nasopharyngeal swabs were tested for RSV using three tests: (1) rapid antigen test (RAT); (2) reverse transcriptase polymerase chain reaction (PCR); or (3) quantitative PCR (RT-qPCR); a positive PCR reaction was considered a confirmed case of RSV. Phylogenetic analysis of the G protein was performed for outbreak and reference samples from non-outbreak periods of the same year. In total, 12 confirmed cases were identified, including 8 hemato-oncology patients. Patient samples were collected weekly, until all confirmed RSV cases returned RSV negative test results. Median time of suspected viral shedding was 16 days (n = 5, range: 8-37 days). Sensitivity and specificity of the RAT compared with RT-qPCR were 30% and 91% (n = 42). Phylogenetic analysis revealed nine genetically identical strains; eight occurring during the outbreak time period and one strain was detected 1 month prior. A genetically similar RSV detected 1 month before is considered one potential source of this outbreak. As such, healthcare providers should always enforce standard precautions, especially in the hemato-oncology unit. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to examine the associations between postoperative clinicopathological features of intraductal papillary mucinous neoplasm (IPMN) and recurrence over a long follow‐up period. Methods: We retrospectively assessed 153 IPMN patients who underwent resection. Results: The resected tumors showed low/intermediate‐grade dysplasia (LGD/IGD), high‐grade dysplasia (HGD), T1a (stromal invasion ≤5 mm), and invasive intraductal papillary mucinous carcinoma (IPMC), in 54.9%, 22.2%, 4.6%, and 18.3% of patients, respectively. The median follow‐up period after surgery was 46.4 (6.0–216.3) months, with an overall recurrence rate of 17.0%; the recurrence rates by histological type were 6.0%, 5.9%, 42.9%, and 57.1% for LGD/IGD, HGD, T1a, and invasive IPMC, respectively. Multivariate analysis revealed that recurrences related with tumor location, mural nodule size, presence of invasive cancer, lymph node metastasis, IPMN in the remnant pancreas, and main pancreatic duct dilatation after surgery. Recurrence occurred within the remnant pancreas in all LGD‐T1a patients and as extrapancreatic metastasis in all patients with invasive IPMC. Of the total recurrences, 15.4% occurred over 5 years postoperatively. Conclusions: The postoperative follow‐up protocol for patients with LGD‐T1a should be similar to non‐resected IPMN, and that for invasive IPMC should be the same as for pancreatic ductal adenocarcinoma patients. Highlight This is the first study evaluating postoperative recurrence patterns of intraductal papillary mucinous neoplasms in detail over a long follow‐up period in accordance with the new International Consensus Guidelines 2012 for the Management of IPMN. On the basis of the results, Yogi and colleagues proposed new follow‐up protocols following resection. [ABSTRACT FROM AUTHOR]

Urgent response is required in suspected pulmonary tuberculosis (PTB) cases for infection control, and chest image is the first step to suspect PTB. This case shows an unexpected exception and importance of molecular testing for definite diagnosis. [ABSTRACT FROM AUTHOR]

NTM‐SPN is often indistinguishable from malignancy. Although surgical resection is sometimes chosen for the diagnosis and treatment, the mass in this case shrank spontaneously. Careful observation is required to avoid unnecessary interventions. [ABSTRACT FROM AUTHOR]

When observing diffuse ground‐glass opacities in both lungs, physicians should consider several diseases, including heart failure, interstitial lung diseases, and pulmonary infections. However, brain diseases rarely cause lung infiltration. We present an instructive case of neurologic pulmonary edema showing a pathological link between the brain and the lung. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Higa et al. (2012) Role of neuraminidase inhibitor chemoprophylaxis in controlling nosocomial influenza: an observational study. Influenza and Other Respiratory Viruses 6(4), 299-303. Background An influenza outbreak might result in disruption of services at acute care setting hospitals. Objectives In this study, we retrospectively evaluated the use of neuraminidase inhibitor chemoprophylaxis for prevention of nosocomial spread of influenza in a university hospital. Patients/Methods During the 3-year study period, 202 index cases of influenza [30 hospitalized patients and 172 healthcare workers (HCW)] and 762 individuals who had had close contact with the index cases (248 hospitalized patients and 514 HCW) were identified. Of these contacts, 416 received neuraminidase inhibitor chemoprophylaxis. Results When both the index cases and the close contacts were hospitalized patients, the incidence of influenza was lower among the close contacts who received chemoprophylaxis than among those who did not (odds ratio, 0·07; confidence interval, 0·01-0·49; P = 0·012). In contrast, when the index cases were HCW, the incidence of influenza was not different between close contacts who did or did not receive chemoprophylaxis. Conclusions This study suggests that chemoprophylaxis might be useful to prevent nosocomial spread of infection between hospitalized patients. [ABSTRACT FROM AUTHOR]

ABSTRACT A 45-year-old man was referred to our hospital with a history of multiple erythematous skin lesions of several months' duration. Blood examination revealed extreme hypoproteinemia and hypoalbuminemia, as well as the presence of antinuclear antibodies. A skin biopsy specimen showed liquefaction degeneration at the dermoepidermal junction and dense lymphocyte and neutrophil infiltration around the vessels and appendages in the upper and middle dermis. Chest X-ray and computed tomography showed a pleural effusion and thoracic paracentesis revealed a mononuclear cell-dominant cell infiltration, suggestive of serositis. Technetium-99 m (99mTc)-labeled human serum albumin scintigraphy and α1-antitrypsin clearance revealed protein leakage along the digestive tracts from the stomach to the jejunum. From the above findings, the patient was diagnosed with systemic lupus erythematosus (SLE) complicated by protein-losing enteropathy (PLE). Treatment with oral prednisolone significantly improved his clinical symptoms and hypoalbuminemia. This case highlighted the utility of 99mTc-labeled human serum albumin scintigraphy and α1-antitrypsin clearance in the diagnosis of PLE. We also present a published work review on PLE associated with connective tissue disease revealing a relatively higher prevalence in patients of Asian ethnicity, including Japanese. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori secretes vacuolating cytotoxin (VacA) that damages the gastric epithelium by erosion and loosening of tight junctions. VacA has also immunosuppressive effects, inhibiting interleukin (IL)-2 secretion by interference with the T cell receptor/IL-2 signaling pathway. This study investigated the effect of VacA on gene expression of T cells. Materials and methods: Gene expression profile of a T cell line, Jurkat, was analyzed by the cDNA microarray technique after VacA challenge. The expression of specific mRNAs was assessed by reverse transcription-polymerase chain reaction. Interleukin (IL)-8 concentrations in culture supernatants and cell surface expression of CD69 were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively. We evaluated nuclear factor-κB (NF-κB) activation in Jurkat cells challenged with VacA by luciferase assay, electrophoretic mobility shift assay, and Western blot analysis. Results: VacA produced two or greater fold up-regulation of expression of 60 genes. Most of these genes were associated with signal transduction, regulation of gene expression, apoptosis, and inflammation. Up-regulation of four genes ( IL8, IL2RA, ICAM1, and CD69) was confirmed. The supernatants of cells incubated with VacA showed significantly higher secretion levels of IL-8 than those incubated without VacA. VacA also induced the cell surface expression of CD69. Since microarray analysis indicated NF-κB was involved in the transcriptional activation of the above genes, we examined NF-κB signaling pathway. VacA activated NF-κB via classical but not alternative pathway. Conclusions: VacA has two paradoxical effects on T cells, immunosuppression, and proinflammatory effects. The latter is mediated by NF-κB activation. [ABSTRACT FROM AUTHOR]

Background and Aim: There have been few studies on the association between human T cell lymphotropic virus type 1 (HTLV-1) infection and cancer risk. It is still controversial whether or not HTLV-1 infection affects the incidence of several cancers. With this background, we aimed to evaluate the relationship between HTLV-1 infection and the occurrence of several types of cancers. Methods: Subjects were 699 patients with cancer aged 50 years and older diagnosed between 1991 and 2004 at the Department of Medicine and Therapeutics, Ryukyu University Hospital, Okinawa, Japan, and 1365 control patients without cancer. The association between HTLV-1 infection and cancer (biliary tract, pancreatic, esophageal, gastric, colorectal, liver, and lung cancers) was analyzed by logistic regression analysis adjusted for age and sex. Results: The infection rate of HTLV-1 in patients with gastric cancer was significantly lower than in controls ( P = 0.01, adjusted odds ratio 0.46). The infection rate of HTLV-1 was not associated with increased or decreased risk of cancers other than gastric cancer. Conclusion: Our study indicated that the prevalence of HTLV-1 infection in patients with gastric cancer appears to be significantly lower than that in control patients. [ABSTRACT FROM AUTHOR]

Objective In this study, we describe the chest computed tomography findings of influenza virus-associated pneumonia in adult patients. Methods Our retrospective study included 12 adult patients who had proven influenza virus - associated pneumonia. Results Out of 12 patients, six were diagnosed as having pure influenza virus pneumonia, five as having bronchopneumonia caused by bacteria associated with influenza A infection, and one as having a cryptogenic organizing pneumonia associated with influenza A infection. Conclusion Radiographic findings of influenza virus pneumonia in adult patients consist of ground-glass attenuation. Localized patchy consolidations were observed in cases of bronchopneumonia. [ABSTRACT FROM AUTHOR]

Recently we have demonstrated the existence of anti-cytokeratin 19 (CK19) antibodies in sera of patients with autoimmune hepatitis (AIH). In the present study, we examined the existence of T lymphocytes specific for CK19 in patients with AIH. The frequency of responders having CK19-specific T lymphocytes was significantly higher in AIH patients than in chronic hepatitis C (CH-C) patients and normal subjects. Furthermore, the stimulation index of proliferative responses of peripheral blood mononuclear cells (PBMCs) was significantly higher in AIH patients than in CH-C patients and normal subjects. The phenotype of proliferating PBMCs specific for CK19 was shown to be predominantly CD4+ T lymphocytes and these CD4+ T lymphocytes had a Th1 subtype. The present findings demonstrate that there is some population of CD4+ T lymphocytes with a Th1 subtype specific for CK19 in peripheral blood of patients with AIH. The Th1-predominat pattern of cytokines may induce cytotoxic T lymphocytes (CTLs) specific for the antigenic peptides derived from the autoantigen, including CK19. In addition, these CTLs may attack the hepatocytes and this may be one of the important etiologies of AIH. [Copyright &y& Elsevier]

Immunopathological differences between autoimmune hepatitis (AIH) and chronic hepatitis C (CH-C) have not been well investigated. Therefore, we immunohistochemically examined the expression of various cytokeratins (CKs) not only in liver tissues of AIH but also in those of CH-C at the active stage. Furthermore, to evaluate the immune surveillance system and the susceptibility to apoptosis, immunohistochemical staining of human leukocyte antigen (HLA)-DRα, cathepsin D, B cell leukemia-2 (bcl-2), bcl-2-associated X protein (bax) and caspase 3 was also performed. Heterogeneous expression of CK 8 and CK 18 was observed in hepatocytes of AIH, while homogeneous expression was observed in hepatocytes of CH-C. Aberrant expression of CK 7 and CK 19 was observed in hepatocytes of AIH, while it was not in hepatocytes of CH-C. Expression of HLA-DRα was observed in hepatocytes of AIH but not in those of CH-C. Furthermore, expression of cathepsin D, bax and caspase 3 was much stronger in hepatocytes of AIH than in those of CH-C. These results indicate that cytoskeletal alterations of hepatocytes in AIH may increase the susceptibility to apoptosis and induce hepatocyte destruction. [Copyright &y& Elsevier]

Please cite this paper as: Sunagawa et al. (2012) Single-dose inhaled laninamivir: registered in Japan and its potential role in control of influenza epidemics. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750-2659.2012.00351.x. [ABSTRACT FROM AUTHOR]

Background: Guidelines for high-level disinfection of gastrointestinal endoscopes have been published in many countries; however, none of them have a statement for disinfection against the parasite Strongyloides stercoralis. To establish a method for gastrointestinal endoscope disinfection against Strongyloides stercoralis, we examined the disinfection efficacy of high-level disinfectants (3% glutaraldehyde, 0.55% ortho-phthalaldehyde, and 0.3% peracetic acid) and 70% ethanol by in vitro tests. Methods: Strongyloides stercoralis larval suspension (0.05 mL) was added to 0.95 mL of each disinfectant and disinfection time measured under low magnification microscopy. Results: Among the high-level disinfectants, peracetic acid was more efficacious for disinfection against Strongyloides stercoralis than glutaraldehyde and ortho-phthalaldehyde. Ethanol was also efficacious for parasite killing. Conclusion: These results suggested that peracetic acid be recommended for gastrointestinal endoscope disinfection in regions with endemic Strongyloides stercoralis. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Fujita et al. (2012) Hamman-Rich syndrome revisited: How to avoid misdiagnosis. Influenza and Other Respiratory Viruses. DOI: 10.1111/j.1750-2659.2012.00353.x. [ABSTRACT FROM AUTHOR]

The article discusses a manifestation of mesenteric lymphoma. It states that mesenteric lymphoma produces a sign which is a soft mass constructing a sandwich-like image composed of fat and vessels. Biopsy of the mass showed B-cell lymphomas indicating that Epstein-Barr virus induced B-cell lymphoproliferation also has the tendency to produce the sandwich sign.

The article presents information on the case of a woman with a history of dermatomyositis-scleroderma overlap syndrome and interstitial pneumonia, presented with abdominal distention. Abdominal radiography showed a revealed marked intestinal dilated loops and the hide-bound bowel sign. Diagnosis revealed chronic intestinal pseudoobstruction. Her symptoms increased with conservative treatment.

Background: Helicobacter pylori secretes vacuolating cytotoxin (VacA) that damages the gastric epithelium by erosion and loosening of tight junctions. VacA has also immunosuppressive effects, inhibiting interleukin (IL)-2 secretion by interference with the T cell receptor/IL-2 signaling pathway. This study investigated the effect of VacA on gene expression of T cells., Materials and Methods: Gene expression profile of a T cell line, Jurkat, was analyzed by the cDNA microarray technique after VacA challenge. The expression of specific mRNAs was assessed by reverse transcription-polymerase chain reaction. Interleukin (IL)-8 concentrations in culture supernatants and cell surface expression of CD69 were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively. We evaluated nuclear factor-kappaB (NF-kappaB) activation in Jurkat cells challenged with VacA by luciferase assay, electrophoretic mobility shift assay, and Western blot analysis., Results: VacA produced two or greater fold up-regulation of expression of 60 genes. Most of these genes were associated with signal transduction, regulation of gene expression, apoptosis, and inflammation. Up-regulation of four genes (IL8, IL2RA, ICAM1, and CD69) was confirmed. The supernatants of cells incubated with VacA showed significantly higher secretion levels of IL-8 than those incubated without VacA. VacA also induced the cell surface expression of CD69. Since microarray analysis indicated NF-kappaB was involved in the transcriptional activation of the above genes, we examined NF-kappaB signaling pathway. VacA activated NF-kappaB via classical but not alternative pathway., Conclusions: VacA has two paradoxical effects on T cells, immunosuppression, and proinflammatory effects. The latter is mediated by NF-kappaB activation.

Legionella pneumophila is the etiologic agent of Legionnaires' disease. This bacterium contains a single monopolar flagellum, of which the FlaA subunit is a major protein constituent. The murine macrophage resistance against this bacterium is controlled by the Birc1e/Naip5 gene, which belongs to the NOD family. We evaluated the intracellular growth of the flaA mutant bacteria as well as another aflagellated fliA mutant, within bone marrow-derived macrophages from mice with an intact (C57BL/6, BALB/c) or mutated (A/J) Birc1e/Naip5 gene. The flaA mutant L. pneumophila multiplied within C57BL/6 and BALB/c macrophages while the wild-type strain did not. Cell viability was not impaired until 3 days after infection when the flaA mutant bacteria replicated 10(2-3)-fold in macrophages, implying that L. pneumophila inhibited host cell death during the early phase of intracellular replication. The addition of recombinant interferon-gamma (IFN-gamma) to the infected macrophages restricted replication of the flaA mutant within macrophages; these treated cells also showed enhanced nitric oxide production, although inhibition of nitric oxide production did not affect the IFN-gamma induced inhibition of Legionella replication. These findings suggested that IFN-gamma activated macrophages to restrict the intracellular growth of the L. pneumophila flaA mutant by a NO independent pathway.

Dectin-1 is known as a sole receptor for beta-glucan, a major cell wall component of fungal microorganisms. In the current study, we examined the role of this molecule in the host defense to Cryptococcus neoformans, an opportunistic fungal pathogen in AIDS patients. There was no significant difference in the clinical course and cytokine production between dectin-1 gene-deficient and control mice. These results indicate that dectin-1 is not likely essential for the development of host protective responses to C. neoformans.

Cryptococcal meningoencephalitis is a life-threatening infectious disease in immunocompromised patients. Unmethylated CpG-oligodeoxynucleotides (CpG-ODN) protects hosts in a mouse model. In the present study, we tested the adjuvant effect of CpG-ODN in anti-fungal chemotherapy. Administration of either fluconazole (FLCZ) or CpG-ODN was effective in extending survival, accelerating clearance of fungi and preventing disseminated infection. Combination of both agents provided more beneficial effect than either agent alone. Cytokine balance in the infected lungs was biased to Th1-type response by CpGODN, while FLCZ did not further promote. These results suggest that CpG-ODN is a promising adjuvant in chemotherapy against this infection.

In a previous study, we demonstrated anti-vimentin antibodies in sera of patients with interstitial pneumonia. We hypothesized that antibodies in sera might detect vimentin fragments formed during the process of apoptosis. To prove this, recombinant human vimentin was digested by recombinant human caspase-3 or caspase-8. Then, Western blotting using several commercially available antibodies against human vimentin or patients' sera which had anti-vimentin autoantibodies, was performed. As a result, after recombinant human vimentin was digested by caspase-3 or caspase-8, several vimentin fragments were formed and detected by 2 kinds of monoclonal anti-vimentin antibodies (clone 3B4 and clone V9) as well as by polyclonal sheep anti-human vimentin antibody. It was demonstrated that high molecular weight vimentin was formed after the digestion of vimentin by caspase-3, which was only detected by patients' sera. The high molecular weight vimentin was not formed after digestion of vimentin by caspase-8. Our present results show that high molecular weight vimentin was formed after the digestion of vimentin by caspase-3. In addition, it is suggested that this high molecular weight vimentin acted as an autoantigen to form anti-vimentin autoantibody in vivo.

The present study was designed to evaluate the distribution of epithelioid cells, myofibroblasts, and TGF-beta1 in the formation of granuloma caused by Mycobacterium avium intracellulare complex (MAC) lung infection. A retrospective study was performed for 9 cases of positive MAC culture in which lung resections were performed between January 1989 and August 1999. Resected lung specimens were evaluated histologically and immunohistochemically for CD68 (stain for monocytes and macrophages, and epithelioid cells) and alpha-smooth muscle actin as well as vimentin (stain for myofibroblasts), and TGF-beta1 was performed. When granuloma was initially formed, no myofibroblasts were found, but as caseous necrosis appeared, the thin epithelioid cell layer was detected and the outer myofibroblast layer gradually became thick. In the cavitary wall, the layer of epithelioid cells and multinucleated giant cells surrounded necrosis, and was associated with the outer layer of myofibroblasts. In addition, the anti-TGF-beta1 antibody stained the cytoplasm of epithelioid cells and multinucleated giant cells, preceding the advent of myofibroblasts. In summary, our present study evaluated distributions of epithelioid cells, myofibroblasts, and TGF-beta along with the morphogenesis of granuloma, and clearly demonstrated the immunohistochemical difference between granuloma with caseous necrosis and granulomas without caseous necrosis.