Clinical features of patients with obsessive-compulsive disorder showing different pharmacological responses]

BACKGROUND: Although selective serotonin reuptake inhibitors (SSRIs) are the mainstay of pharmacological treatment for obsessive-compulsive disorder (OCD), some OCD patients do not show improvement. Sometimes, the addition of a low-dose atypical antipsychotic, such as risperidone, or olanzapine, to ongoing SSRI treatment has been shown to be effective. However, there are patients who still show no response after trials with this augmentation therapy. In the present study, we examined the clinical features of OCD patients who showed different responses to pharmacological treatment. SUBJECTS AND METHOD: Fifty OCD patients were divided into three groups according to their pharmacological responses: responders to SSRI (group A: n= 25), responders to SSRI with an atypical antipsychotic (group B: n= 15), and non-responders to both SSRI and SSRI with an atypical antipsychotic (group C: n= 10). We examined the clinical features such as age, sex, age of onset, duration of illness, types of obsessive-compulsive symptoms, severity, improvement after treatment, insight into disease, depression, comorbidity, involving family members in compulsive or ritualistic behavior, and the level of social adaptation of each OCD group. RESULTS: Twenty five patients showed a good response to SSRI monotherapy, 15 showed a response to antipsychotic augmentation, and 10 were non-responders to both SSRI and SSRI with an atypical antipsychotic. Significantly lower insight levels were observed only in group B and higher depressive levels in group C. OCD patients who were refractory to SSRI monotherapy showed comorbidity at a significantly higher frequency. OCD patients in group A showed significantly greater improvement, and group B showed inferior social adaptation after treatment. There were no significant differences in age, sex, age of onset, duration of illness, severity, involving family members in compulsive or ritualistic behavior, and social adaptation before treatment in the three OCD groups. CONCLUSION: There were differences in the clinical features of OCD patients who showed different responses to pharmacological treatment. Our results suggest that OCD is clinically and biologically heterogeneous. It may be important to divide OCD patients into subgroups for future studies.     

Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human matrix Gla protein (MGP) locus

Matrix Gla protein (MGP) is an 84-residue, vitamin K-dependent protein expressed by chondrocytes and vascular smooth muscle cells, and is a potent regulator of calcium deposition in cartilage and arterial wall. We isolated a polymorphic dinucleotide CA repeat marker from a genomic clone containing the human MGP gene. This polymorphism will be useful in genetic studies of arteriosclerosis and osteoporosis. Received: November 5, 1997 / Accepted November 27, 1997     

Isolation of a polymorphic CA repeat sequence at the human progesterone receptor (PGR) locus

We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the human progesterone receptor (PGR) gene. This polymorphism will be a useful marker in the genetic study of disorders affecting female endocrine systems, such as progesterone resistance and breast, uterine, and ovarian cancers. Received: July 27, 1998 / Accepted: July 29, 1998     

Isolation and radiation hybrid mapping of a dinucleotide repeat polymorphism at the human calcium-sensing receptor (CASR) locus

Calcium-sensing receptor (CASR) in parathyroid gland regulates calcium homeostasis by sensing decreases in extracellular calcium levels and effecting an increase in secretion of parathyroid hormone. A polymorphic dinucleotide (CA) sequence was isolated from a genomic clone containing the human CASR gene and was mapped to 3q13.3–q21. This polymorphism will be useful in the genetic study of disorders affecting calcium metabolism, such as hypercalcemia, hypocalcemia, osteoporosis, hyperparathyroidism, and hypoparathyroidism. Received: June 2, 1998 / Accepted: June 24, 1998     

Interferon-gamma production by human cord blood monocyte-derived dendritic cells

Interferon (IFN)-gamma is produced by T cells and natural killer cells and activates monocytes and dendritic cells (DCs). Recently, IFN-gamma has been shown to be produced by mouse DCs following stimulation with interleukin (IL)-12, which is markedly augmented by the addition of IL-18. We here analyzed whether human DCs secrete IFN-gamma in response to IL-12 and/or IL-18. Human immature DCs, generated from cord blood CD14(+) monocytes by treating with granulocyte-macrophage colony-stimulating factor and IL-4, were incubated with IL-12 and/or IL-18 and assayed for IFN-gamma production. IL-12, but not IL-18, weakly induced IFN-gamma production, while IL-12 together with IL-18 induced high levels of IFN-gamma production. Similar results were obtained with mature DCs, although levels of IFN-gamma production were less than those in immature DCs. Also with mature and immature DCs, IL-12 upregulated the expression of IL-18 receptor alpha (Ralpha), and costimulation with IL-12 and IL-18 upregulated CD40 expression. Anti-IL-18Ralpha antibody abrogated both the IFN-gamma induction and the CD40 upregulation by IL-12 plus IL-18. These findings suggest that IL-12 upregulates IL-18Ralpha expression on human DCs and acts synergistically with IL-18 to induce high levels of IFN-gamma, which subsequently enhances CD40 expression on DCs in an autocrine manner.     

Potentiation of the ligand-binding activity of integrin alpha3beta1 via association with tetraspanin CD151

CD151, one of the tetraspanins, forms a stable complex with integrin alpha3beta1, the major laminin receptor on the cell surface. We found that 8C3, an anti-CD151 mAb obtained by screening for reactivity with integrin alpha3beta1-CD151 complexes, was capable of dissociating CD151 from integrin alpha3beta1, thereby allowing us to deplete CD151 from purified integrin alpha3beta1-CD151 complexes. The CD151-free integrin alpha3beta1 thus obtained showed a significant reduction in its ability to bind to laminin-10/11, a high-affinity ligand for integrin alpha3beta1, with a concomitant reduction in its reactivity with mAb AG89, which recognizes activated beta1-containing integrins. These results raised the possibility that the association of integrin alpha3beta1 with CD151 potentiates the ligand-binding activity of the integrin through sustaining its activated conformation. In support of this possibility, the ligand-binding activity was restored when CD151-free integrin alpha3beta1 was reassociated with purified CD151. 8C3-induced dissociation of CD151 from integrin alpha3beta1 was also demonstrated on the surface of living cells by fluorescent resonance energy transfer imaging, accompanied by a concomitant reduction in the cell adhesion to laminin-10/11-coated substrates. CD151 knock-down by RNA interference also resulted in a reduction in the adhesive activity of the cells. Taken together, these results indicate that CD151 association modulates the ligand-binding activity of integrin alpha3beta1 through stabilizing its activated conformation not only with purified proteins but also in a physiological context.     

Lack of association of interleukin-18 gene polymorphisms with susceptibility of Japanese populations to Graves' disease or Graves' ophthalmopathy.

OBJECTIVE: To investigate whether polymorphisms of interleukin (IL)-18 gene confer susceptibility to Graves' disease (GD) and Graves' ophthalmopathy (GO). DESIGN: We performed a case control study on polymorphisms of IL-18 gene in Japanese patients with GD (n = 435), and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 255). The C-4675G, C-607A, and G-137C polymorphisms in the promoter region and A105C (exon 5) polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using restriction enzymes, sequence-specific PCR, and PCR-direct sequencing methods. RESULTS: None of the polymorphisms in the IL-18 gene were associated with development of Graves' disease. The CC genotype and C allele frequencies of IL-18 gene G-137C polymorphism tended to be greater in patients with ophthalmopathy than in patients without evident ophthalmopathy. However, the differences were not statistically significant. Although there were three major haplotypes, none of the haplotypes were statistically associated with susceptibility to GD or ophthalmopathy. CONCLUSIONS: These results suggest that IL-18 gene polymorphisms are not major genetic factors for susceptibility to GD in a Japanese population. Further studies with adequate sized data set in the subset analyses for GO are needed.     

PPARγ ligand attenuates portal inflammation in the MRL-lpr mouse: a new strategy to restrain cholangiopathy in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by chronic destructive cholangitis, which is associated with the reduced expression of an anti-inflammatory molecule, peroxisome proliferator-activated receptor-γ (PPARγ), in intrahepatic bile ducts. We previously demonstrated the anti-inflammatory effects of PPARγ ligands using cultured human biliary epithelial cells. In this study, we evaluated the effectiveness of PPARγ ligand against peribiliary inflammation in vivo. As an animal model of PBC, we used MRL/lpr mice in which a PBC-like cholangitis occurs naturally. Anti-inflammatory effects of the intraperitoneal administration of a PPARγ ligand, the prostaglandin D metabolite 15-deoxy-Δ^12,14-prostaglandin J2 (15d-PGJ2), were evaluated. In untreated mice, portal inflammation including cholangitis was found to some degree in the majority of portal tracts. In mice given a high-dose group, the degree of portal inflammation was significantly reduced and mice mostly lacking portal inflammation and cholangitis were also found. T cell numbers in portal tracts were markedly decreased in the high-dose group, compared with controls, whereas there was no significant difference in terms of B cells and macrophages. This study is the first to assess the therapeutic potential of a PPARγ ligand against portal inflammation including cholangitis. Anti-inflammatory effects of PPARγ ligands may prevent the progression of cholangiopathy in PBC patients.