Autoimmune hepatitis complicated with antiphospholipid syndrome in pregnancy

PROBLEM: There are few reports on the association between autoimmune hepatitis (AIH) and antiphospholipid syndrome; only five reports were found on a MEDLINE search between 1966 and 2001. Therefore, the etiology and the optimal treatment of them are not clear. METHOD OF STUDY: We encountered a case of AIH complicated by antiphospholipid syndrome in pregnancy. We present the clinical course and treatment of this case, and discuss some problems in managing such a patient. RESULTS: The patient received low-dose prednisolone and low-dose aspirin and delivered a live-born infant at term without any adverse effects. CONCLUSION: In this case, there was no relation between the variation of alanine aminotransferase (ALT) and the one of beta2-glycoprotein I (GPI)-dependent anticardiolipin antibody. It is supposed that there was no relation between the activity of AIH and the one of antiphospholipid syndrome, and it is also supposed that one is not secondary to the other.     

Assistance for improving QOL of patients with terminal disease cared at home

A visiting nursing service was provided for a female patient with the terminal stage of transverse colon cancer. The patient, who strongly wanted to stay at home, was discharged from hospital under continuous subcutaneous injection of morphine hydrochloride in late April 2001. The visiting nurse supported her life including the procedures for the continuous subcutaneous injection for attenuating pain as the main symptom. As a result, her fear of pain was reduced and she became able to control pain by oral medication. She became able to walk to the rest room and take a shower and have increased ADL while regaining the strength of will. Family members were concerned with the potential sudden change in her conditions or intensification of pain at home but the worry was contained by understanding the procedures to follow in such cases. QOL can be improved even at the terminal stage if: 1. the patient understand the pathological condition; 2. the patient discloses his/her worry; 3. the patient can choose the way of living; 4. caregiver can cope with the change; 5. caregiver can maintain the nursing capability; 6. the medical provider's assistance system is established.     

Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma

A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal‐naïve patients with relapsed or refractory multiple myeloma (RRMM). Patients ≥20 and <80 years old with a documented diagnosis of symptomatic multiple myeloma (MM) who received one or more prior therapies were randomized to receive BD (Bor 1.3 mg/m²) or TD (Thal 200 mg/d). In both arms, 8 cycles of induction (3‐week cycle) were followed by maintenance phase (5‐week cycle) until disease progression, unacceptable toxicity, or patient refusal. The primary end‐point was 1‐year progression‐free survival (PFS). Forty‐four patients were randomized and assigned to receive BD and TD (n = 22, each group). At a median follow‐up of 34.3 months, the 1‐year PFS in the BD and TD arms were 45.5% (95% confidence interval (CI), 24.4%‐64.3%) and 31.8% (95% CI, 14.2%‐51.1%), respectively, and the overall response rates were 77.3% and 40.9%, respectively. The 3‐year overall survival (OS) was 70.0% (95% CI, 44.9%‐85.4%) in the BD, and 48.8% (95% CI, 25.1%‐69.0%) in the TD arm. Among grade 3/4 adverse events, thrombocytopenia (54.5% vs 0.0%) and sensory peripheral neuropathy (22.7% vs 9.1%) were more frequent in BD when compared with the TD arm. Patients treated with BD had better outcomes than those treated with TD with regard to 1‐year PFS and 3‐year OS. Thus, BD was prioritized over TD for further investigations in Bor and Thal‐naïve RRMM patients. (Clinical trial registration no. UMIN000003135.)     

Hyperimmunoglobulinemia D in idiopathic retinal vasculitis

Background: We examined four patients who exhibited both idiopathic retinal vasculitis and elevated serum IgD levels. Uveitis caused by Behçet's disease is also associated with high levels of serum IgD. Therefore, the clinical features of these patients were investigated and the possible relationship between retinal vasculitis and elevated serum IgD was examined after undertaking a study of increased IgD levels in patients diagnosed with uveitis. Methods: The study population was composed of 110 patients: 49 with Behçet's disease, 15 with sarcoidosis, 10 with Vogt-Koyanagi-Harada disease, and 36 with other forms of uveitis. IgD measurements were performed using modifications of the latex photometric immunoassay. Surface IgD (sIgD) expression in peripheral lymphocytes was determined by immunofluorescence, and the correlation between serum IgD levels and the percentage of sIgD-positive cells was examined. Results: Twelve of the 110 patients had an elevated serum IgD. Eight of the 12 had Behçet's disease, and 4 were diagnosed with idiopathic retinal vasculitis. These 4 patients were HLA-A24+ females whose ages ranged from 8 to 25 years. A linear correlation between the serum IgD levels and the percentage of sIgD-positive cells was found. Conclusion: Hyperimmunoglobulinemia D state was found in Behçet's disease and idiopathic retinal vasculitis. These diseases may represent a new clinical entity characterized by signs of retinal vasculitis and hyperimmunoglobulinemia D that results from abnormal B cell activation and immune complex-mediated responses.     

Relationship between leukotriene C4 and an uteroglobin-like protein in nasal and tracheobronchial mucosa of children. Implication in acute respiratory illnesses

Secretions from the nose and nasopharynx (NPS) are more readily accessible than tracheobronchial secretions (TBS) for clinical investigations, but it is unclear whether changes in mediator release in the nasopharynx reflect similar changes in the tracheobronchial tree. In order to clarify this question, NPS and TBS were taken from 20 children with tracheotomy and tested for the presence of leukotriene C4 (LTC4) and uteroglobin-like protein (UTG-LP). LTC4 and UTG-LP were measured both when the children were healthy and when they had clinical evidence of an acute respiratory tract illness. The mean concentration of LTC4 in NPS and TBS increased during illness although the mean concentration in NPS was significantly higher than in TBS during respiratory illness. In healthy children UTG-LP was detected only in TBS. During acute respiratory illness the concentration of UTG-LP in TBS decreased but remained significantly higher than in NPS. Data presented in this study indicate that changes in the LTC4 concentration in NPS appear to reflect changes in LTC4 concentration in TBS although the levels of LTC4 in NPS were significantly higher than in TBS. An inverse correlation between the concentrations of LTC4 and UTG-LP in NPS and TBS was demonstrated.     

Evaluation of the suppressive actions of glucosamine on the interleukin-1β-mediated activation of synoviocytes

Objective: Recently, we found that administration of glucosamine to adjuvant arthritis, a model for rheumatoid arthritis, suppressed the progression of arthritis in rats. To clarify its anti-inflammatory mechanism, we evaluated the actions of glucosamine on the activation of synoviocytes in vitro. Materials and methods: Synoviocytes isolated from human synovial tissues were stimulated with interleukin (IL)-1β in the presence of 0.01–1 mM glucosamine. IL-8 and prostaglandin (PG) E₂ were measured by ELISA, and nitric oxide was quantitated by Griess assay. IL-8 mRNA was detected by RT-PCR. Furthermore, the effect of glucosamine on the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the binding of [¹²⁵I] IL-1β to its receptors were examined using a primary human synovial cell line (CSABI- 479). Results: Glucosamine significantly suppressed the IL-1β-induced IL-8 production as well as its mRNA expression (p < 0.05) at 1 mM. Furthermore, glucosamine (1 mM) inhibited the IL-1β-induced nitric oxide and PGE₂ production (p < 0.05). Moreover, glucosamine suppressed the IL-1β-induced phosphorylation of p38 MAPK (p < 0.05 at >0.1 mM) and the IL-1β-binding to its receptors (p < 0.05 at 1 mM). Conclusions: These observations suggest that glucosamine can suppress the IL-1β-mediated activation of synoviocytes (such as IL-8-, nitric oxide- and PGE₂-production, and phosphorylation of p38 MAPK), thereby possibly exhibiting antiinflammatory actions in arthritis. Received 5 February 2007; returned for revision 20 March 2007; accepted by M. Katori 8 June 2007     

Effective and safe gene therapy for colorectal carcinoma using the cytosine deaminase gene directed by the carcinoembryonic antigen promoter.

We have recently isolated carcinoembryonic antigen (CEA) promoter regions consisting of 419 bp and 204 bp from CEA-producing human colorectal carcinoma (CRC). We constructed CEA419/CD and CEA204/CD retroviruses carrying the bacterial cytosine deaminase (CD) gene directed by the CEA promoter regions. pCD2 retroviruses carrying the CD gene directed by the retrovirus long terminal repeat promoter were also used. CEA419/CD or CEA204/CD retrovirus-infected CRC cells were found to be susceptible to 5-fluorocytosine (5-FC), while non-CRC cells infected with the same retroviruses were not. CD-transduced CRC xenografts in nude mice were sensitive to 5-FC treatment, resulting in arrest of tumor growth. When mice with intraperitoneally disseminated CRCs were given intraperitoneal injections of CEA419/CD retrovirus-producing cells followed by 5-FC treatment, significantly prolonged survival rates were observed compared with animals injected with pCD2 retrovirus-producing cells followed by 5-FC treatment. Importantly, bone marrow suppression was not observed in animals injected with CEA419/CD retrovirus-producing cells and 5-FC, while profound bone marrow suppression was observed in those injected with pCD2 retrovirus-producing cells and 5-FC. These results indicate that effective and safe in vivo gene therapy for advanced CRC may be feasible by transferring the CD gene controlled by the CEA promoter followed by 5-FC treatment.     

Development of an ex vivo cellular model of rheumatoid arthritis: Critical role of cd14‐positive monocyte/macrophages in the development of pannus tissue

Objective

To establish an ex vivo cellular model of pannus, the aberrant overgrowth of human synovial tissue (ST).

Methods

Inflammatory cells that infiltrated pannus tissue from patients with rheumatoid arthritis (RA) were collected without enzyme digestion, and designated as ST‐derived inflammatory cells. Single‐cell suspensions of ST‐derived inflammatory cells were cultured in medium alone. Levels of cytokines produced in culture supernatants were measured using enzyme‐linked immunosorbent assay kits. ST‐derived inflammatory cells were transferred into the joints of immunodeficient mice to explore whether these cells could develop pannus. CD14 and CD2 cells were depleted by negative selection.

Results

Culture of ST‐derived inflammatory cells from 92 of 111 patients with RA resulted in spontaneous reconstruction of inflammatory tissue in vitro within 4 weeks. Ex vivo tissue contained fibroblasts, macrophages, T cells, and tartrate‐resistant acid phosphatase–positive multinucleated cells. On calcium phosphate–coated slides, ST‐derived inflammatory cell cultures showed numerous resorption pits. ST‐derived inflammatory cell cultures continuously produced matrix metalloproteinase 9 and proinflammatory cytokines associated with osteoclastogenesis, such as tumor necrosis factor α, interleukin‐8, and macrophage colony‐stimulating factor. More importantly, transferring ST‐derived inflammatory cells into the joints of immunodeficient mice resulted in the development of pannus tissue and erosive joint lesions. Both in vitro development and in vivo development of pannus tissue by ST‐derived inflammatory cells were inhibited by depleting CD14‐positive, but not CD2‐positive, cells from ST‐derived inflammatory cells.

Conclusion

These findings suggest that overgrowth of inflammatory cells from human rheumatoid synovium simulates the development of pannus. This may prove informative in the screening of potential antirheumatic drugs.