Jungsu S. Oh

Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes

OBJECTIVE Advanced glycation end products (AGE) accumulate in articular cartilage with age. We investigated the effects of AGE in primary-cultured human OA chondrocytes. METHODS Chondrocytes were cultured with/or without AGE-bovine serum albumin (AGE-BSA) and the expression levels of inducible nitric oxide (iNOS), cyclooxygenase (COX)-2 microsomal prostaglandin E synthase-1 (mPGES-1) were evaluated using RT-PCR and western blot analysis. Prostaglandin E(2) (PGE(2)) was analysed by ELISA and nitric oxide (NO) was analysed by Griess reaction assay. Pharmacological studies to elucidate the involved pathway were executed using specific inhibitors of MAPK and receptor for AGE (RAGE). RESULTS We found that treatment of OA chondrocytes with AGE-BSA increased COX-2, mPGES-1 and iNOS mRNA and protein, as well as elevating production of PGE(2) and NO. Pre-treatment with the MAPK inhibitors SP600125 (JNK inhibitor), SB202190 (p38 inhibitor) or PD98059 (ERK inhibitor) significantly inhibited AGE-BSA induction of COX-2 expression and production of PGE(2). In contrast, SN50, a nuclear factor-kappaB (NF-kappaB) inhibitor, had no effect on levels of COX-2 and PGE(2). SB202190 and SN50, but not SP600125 and PD98059, decreased AGE-BSA-induced production of NO. Pre-treatment with soluble receptor for AGE (sRAGE) also reduced AGE-stimulated COX-2, iNOS and PGE(2), implicating the involvement of RAGE. CONCLUSIONS These results show that AGE may augment inflammatory responses in OA chondrocytes by increasing PGE(2) and NO levels, possibly via the MAPK pathway for PGE(2) and the NF-kappaB pathway for NO.

Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease

Objective: To investigate whether the magnitude of presynaptic dopamine depletion is a risk factor for the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) by quantitatively analyzing 18F-FP-CIT PET data. Methods: This retrospective cohort study enrolled a total of 127 drug-naive de novo patients with PD who completed 18F-FP-CIT PET scanning at their initial evaluation. The patients visited our outpatient clinic every 3–6 months and had been followed for a minimum of 2 years since beginning dopaminergic medication. The predictive power of the quantitatively analyzed 18F-FP-CIT uptake of striatal subregions and other clinical factors for the development of LID was evaluated using Cox proportional hazard models. Results: During a mean follow-up period of 3.4 years, 35 patients with PD (27.6%) developed LID. Patients with LID showed less dopamine transporter (DAT) activity in the putamen than did those without LID. Multivariate Cox proportional hazard models revealed that the DAT uptakes of the anterior putamen (hazard ratio [HR] 0.530; p = 0.032), posterior putamen (HR 0.302; p = 0.024), and whole putamen (HR 0.386; p = 0.022) were significant predictors of the development of LID, whereas DAT activities in the caudate and ventral striatum were not significantly correlated with the development of LID. In addition, younger age at onset of PD and higher dose of levodopa were also significant predictors of the development of LID. Conclusions: The present results provide convincing evidence that presynaptic dopaminergic denervation in PD plays a crucial role in the development of LID.

The difference between lupus nephritis class IV-G and IV-S in Koreans: focus on the response to cyclophosphamide induction treatment

OBJECTIVES To evaluate the response to induction therapy with intravenous (i.v.) cyclophosphamide (CYC) in Korean patients with class IV-G (diffuse global proliferative glomerulonephritis) and class IV-S (diffuse segmental proliferative glomerulonephritis) lupus nephritis (LN) according to the classification system of the International Society of Nephrology/Renal Pathology Society (ISN/RPS). METHODS Of the 52 patients with biopsy-proven diffuse proliferative LN, who had been treated with i.v. CYC over a 10-yr period, 42 had been treated with i.v. CYC (equal to or more than 500 mg) for 6 consecutive months and had biopsy specimens containing more than nine glomeruli. The renal pathology of these 42 patients was reclassified according to the International Society of Nephrology and the Renal Pathology Society 2003 classification, and their renal response rates and laboratory indices after induction therapy were analysed. RESULTS Of the 42 patients assessed, 30 (71%) had IV-G and 12 (29%) had IV-S. Pre-treatment 24 h urinary protein was significantly higher and pre-treatment concentration of anti-dsDNA antibody was significantly lower in IV-G than in IV-S patients. Following induction therapy, complete remission rates were significantly higher in patients with IV-S (67%, 8/12) than in patients with IV-G (33%, 10/30) LN. CONCLUSIONS Class IV-G LN responded more poorly to induction therapy with i.v. CYC pulse than class IV-S LN.

Serum cholesterol in idiopathic and lupus-related protein-losing enteropathy.

Abstract The characteristics of protein-losing enteropathy were evaluated in patients with systemic lupus erythematosus. Among the patients with systemic lupus erythematosus (n = 380) in a tertiary hospital, we reviewed the records of seven patients with generalized edema, hypoalbuminemia without proteinuria and positive results on 99mTc-labelled human serum albumin scintigrams. Patient characteristics and laboratory findings were compared between these seven patients and patients with lupus enteritis (n = 15) or idiopathic protein-losing enteropathy (n = 11). Compared with the lupus enteritis patients, the erythrocyte sedimentation rate and serum total cholesterol levels were significantly increased in patients with systemic lupus erythematosus–related protein-losing enteropathy. Compared with idiopathic protein-losing enteropathy patients, the level of serum total cholesterol was significantly increased, but the level of serum albumin was decreased in patients with systemic lupus erythematosus–related protein-losing enteropathy. Among patients with systemic lupus erythematosus–related protein-losing enteropathy, four patients had high serum total cholesterol levels (≥248 mg/dL) and achieved complete remission after receiving high doses of steroid treatment. However, three patients who had low serum total cholesterol levels (≤219 mg/dL) responded poorly to the steroid-only treatment, and could achieve complete remission only after 3 months of cyclophosphamide pulse treatment with concurrent corticosteroid therapy. The levels of serum total cholesterol are intriguing feature in systemic lupus erythematosus–associated protein-losing enteropathy patients.

Is normosmic Parkinson disease a unique clinical phenotype

Objective: Olfactory dysfunction is present in the majority of patients with early-stage Parkinson disease (PD) and can precede the onset of motor symptoms by many years. We performed this study to evaluate whether normosmic patients with PD had different clinical features compared to hyposmic patients. Methods: We analyzed the data of 208 de novo patients with PD (mean age, 65.4 ± 9.7 years; range, 38–85 years; 104 men) who underwent both olfactory function tests and dopamine transporter (DAT) scans. Results: Normosmic patients were significantly younger and had fewer motor deficits than hyposmic patients with PD. Striatal subregional DAT activities were comparable between the 2 groups, but intersubregional gradients were significantly higher in normosmic than hyposmic PD. A general linear model showed that normosmic patients with PD showed significantly fewer motor deficits after controlling the patients age, sex, symptom duration, and DAT activity in the posterior putamen (p = 0.016). Levodopa-equivalent dose at approximately 2.5 years follow-up tended to be lower in normosmic than in hyposmic PD (p = 0.055). Conclusions: These results suggest that normosmic PD is a unique clinical phenotype with a more benign course, compared to hyposmic PD. Either less pathologic involvement in the olfactory system or a greater potential for olfactory neurogenesis in normosmic PD may contribute to this benign process compared to hyposmic PD.

Cerebellum-specific 18F-FDG PET analysis for the detection of subregional glucose metabolism changes in spinocerebellar ataxia.

The cerebellum (CB) consists of complex anatomical and functional subregions. To better investigate the complicated functional anatomy, a detailed subregional analysis and/or a precise spatial normalization of the fluorine-18 fluorodeoxyglucose (18F-FDG) PET imaging data are essential. Here, the 28 MRIcron CB volumes of interests (VOIs) template merged into eight cerebellar subregional VOIs (bilateral anterior, superior, and inferior posterior lobes of the CB cortex, and the superior and inferior vermis) on mean 18F-FDG PET templates. We also developed a new spatial normalization method using a study-specific and CB-specific template (CBSST) to better localize the VOIs and to minimize interparticipant differences for the locations of whole and subregional CB VOIs, as well as to increase the accuracy of the subregional mean 18F-FDG uptake. Using VOIs of individual 18F-FDG PET images normalized to the 18F-FDG template, we analyzed subregional cerebellar glucose metabolism in patients with spinocerebellar ataxia, a representative disease involving the spinocerebellum, and compared them with age-matched and sex-matched healthy normal controls. We achieved significant improvement over the Montreal Neurological Institute template in spatial normalization accuracy using our CBSST approach for CB VOI location agreement increases (79 vs. 90%) and VOI uptake error decreases in many CB subregions. We also found significant decreases in the anterior/posterior ratio of 18F-FDG uptake in patients with spinocerebellar ataxia (0.45) compared with those in normal controls (0.73) only using our CBSST approach. Therefore, we established an accurate CB subregional VOI analysis framework, and this may be useful for understanding and differentiating many of the cerebellar ataxia diseases.

Successful treatment of recurrent lupus enteritis with rituximab

Sir, A 23-year-old Korean woman was admitted to our hospital in August 2007 with a 4-day history of abdominal pain associated with nausea and vomiting. Three years prior to admission she had been diagnosed with systemic lupus erythematosus (SLE) based on malar rash, lymphocytopenia, positive anti-nuclear antibody, anti-Ro antibody, and anti-double-stranded (ds)DNA antibody. Antiphospholipid antibodies including lupus anticoagulant, anti-cardiolipin antibodies (immunoglobulin [Ig]M and IgG), beta2-glycoprotein I antibodies (IgM and IgG) were all negative on two repeated tests. Prior to this admission, the patient had experienced six episodes of recurrent lupus enteritis from May 2005 to July 2007. With each episode of lupus enteritis, she complained of abdominal pain with or without vomiting and diarrhea, and enhanced computed tomography (CT) scans of the abdomen showed diffuse mucosal edema and bowel wall thickening involving the small and large intestine (target-like appearance) with variable amounts of ascites (Figure 1). Laboratory findings at each admission were unremarkable except for hypocomplementemia. On each occasion, she completely recovered after intravenous (IV) treatment with high-dose steroids (methylprednisolone 1mg/kg/day) and conservative treatments including bowel rest and IV fluids. After the third episode of recurrent lupus enteritis, she received mycophenolate mofetil (MMF) until the fourth episode, and was treated with oral cyclophosphamide (CYC) for 3 months, followed by azathioprine (AZA) for 4 months. However, she experienced two more episodes of recurrent lupus enteritis until July 2007. At the seventh admission for lupus enteritis in August 2007, we decided to administer rituximab 500mg per week IV for 2 consecutive weeks in addition to high-dose steroids. The patient’s absolute CD19 count was 36.7/mm at the time of the first infusion, which decreased to 17.4/mm at 2 weeks after the first rituximab infusion. In September 2007, 3 weeks after the first infusion, the lupus enteritis recurred and high-dose methylprednisolone (2mg/kg/day IV) was administered. At four weeks after the first rituximab infusion, the patient’s CD19 count decreased to 3.1/mm. Thereafter, with gradual tapering of oral corticosteroids, no further lupus enteritis relapse occurred. At 6 months after the first infusion, the patient’s CD19 count was increased to 47.3/mm. For fear of possible relapse of lupus enteritis, she wanted repeated infusion of rituximab rather than observation without rituximab therapy. She received a second cycle of rituximab with concomitant methylprednisolone 100mg/day IV. At 7 months after this second infusion, with a CD19 count of 52.3/mm, the patient received a third cycle of rituximab with concomitant methylprednisolone. In December 2008, 15 months after discharge, the oral methylprednisolone was tapered off and no subsequent symptoms and signs of lupus flare have been reported (Figure 2). Lupus enteritis is one of the most serious complications of SLE. High doses of steroids are required and surgical intervention is indicated if extensive bowel infarction or perforation occurs. Antiphospholipid antibody syndrome can induce intestinal ischemia or infarction and cause symptoms similar to those of mesenteric vasculitis. In our patient, there was no evidence of anti-phospholipid antibodies or thrombosis, and diffuse mucosal edema with bowel wall thickening (target-like appearance) and complete reversibility after immunosuppressive treatments were strongly indicative of intestinal ischemia secondary to mesenteric vasculitis. The recommended initial treatment for lupus enteritis is high-dose parenteral steroids together with complete bowel rest. However, relapse is not uncommon, even in patients who show a good initial response to this treatment. Recently, a case of severe relapsing lupus enteritis treated successfully with a combination of CYC and rituximab was reported. This patient remained free of relapse for 2 years after treatment with two cycles of intra-venous (IV) methylprednisolone 100mg rituximab 500mg IV and CYC 500mg IV. However, the use of single-agent rituximab in lupus enteritis has not been reported. Rituximab is a chimeric monoclonal antibody directed against the CD20 molecule present on B lymphocytes. Several reports have described the use of rituximab to successfully treat refractory lupus Correspondence to: Yong-Gil Kim, Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388–1 Pungnap-dong, Songpa-gu, Seoul 138–736, Korea. E-mail: bestmd2000@amc.seoul.kr Received 9 April 2009; accepted 4 June 2009

Association of body mass index and the depletion of nigrostriatal dopamine in Parkinson's disease

Several antecedent studies had reported close relationship between low body weight and Parkinsons disease (PD). However, there have been few investigations about the role of body weight to nigrostriatal dopaminergic neurodegeneration. This study enrolled 398 de novo patients with PD whom underwent [18F] N-(3-Fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scan and body mass index (BMI) measurement. The relationships between BMI and dopamine transporter (DAT) activity were analyzed using linear regression analysis. A multivariate analysis adjusted for age, gender, disease duration, smoking status, coffee and tea consumption, and residence area revealed that BMI remained independently and significantly associated with DAT activity in all striatal subregions. Moreover, multiple logistic regression analyses showed that BMI was a significant predictor for the lowest quartile of DAT activity in the anterior putamen, ventral striatum, caudate nucleus, and total striatum. The present findings suggest that a low BMI might be closely associated with low density of nigrostriatal dopaminergic neurons in PD, which could support the evidence for the role of low body weight to PD-related pathologies.

Different loss of dopamine transporter according to subtype of multiple system atrophy

PurposeThe aim of this study was to evaluate whether striatal dopamine transporter (DAT) loss as measured by 18F-fluorinated-N-3-fluoropropyl-2-b-carboxymethoxy-3-b-(4-iodophenyl) nortropane ([18F]FP-CIT) PET differs according to the metabolic subtype of multiple system atrophy (MSA) as assessed by [18F]FDG PET.MethodsThis retrospective study included 50 patients with clinically diagnosed MSA who underwent [18F]FP-CIT and [18F]FDG brain PET scans. The PET images were analysed using 12 striatal subregional volume-of-interest templates (bilateral ventral striatum, anterior caudate, posterior caudate, anterior putamen, posterior putamen, and ventral putamen). The patients were classified into three metabolic subtypes according to the [18F]FDG PET findings: MSA-Pm (striatal hypometabolism only), MSA-mixedm (both striatal and cerebellar hypometabolism), and MSA-Cm (cerebellar hypometabolism only). The subregional glucose metabolic ratio (MRgluc), subregional DAT binding ratio (BRDAT), and intersubregional ratio (ISRDAT; defined as the BRDAT ratio of one striatal subregion to that of another striatal subregion) were compared according to metabolic subtype.ResultsOf the 50 patients, 13 presented with MSA-Pm, 16 presented with MSA-mixedm, and 21 presented with MSA-Cm. The BRDAT of all striatal subregions in the MSA-Pm and MSA-mixedm groups were significantly lower than those in the MSA-Cm group. The posterior putamen/anterior putamen ISRDAT and anterior putamen/ventral striatum ISRDAT in the MSA-Pm and MSA-mixedm groups were significantly lower than those in the MSA-Cm group.ConclusionPatients with MSA-Pm and MSA-mixedm showed more severe DAT loss in the striatum than patients with MSA-Cm. Patients with MSA-Cm had more diffuse DAT loss than patients with MSA-Pm and MSA-mixedm.

Systemic lupus erythematosus complicated by acquired von Willebrand’s syndrome

Haematological abnormalities are common in systemic lupus erythematosus (SLE). In some cases of acquired von Willebrand syndrome (AvWS), von Willebrand disease (vWD) is associated with autoimmune or lymphoproliferative disorders. In this study, we describe a 36-year-old woman with SLE and AvWS. The patient was referred to our hospital because of easy bruisability and recurrent vaginal bleeding. She had no history of bleeding tendency and no family history of bleeding diathesis, but she had a history of recurrent arthralgia, photosensitivity and sicca symptoms. Tests for antinuclear, anti–double stranded DNA, anticardiolipin and anti–β2-glycoprotein I antibodies were all positive. Analysis of haemostatic parameters showed complete absence of von Willebrand factor ristocetin cofactor (vWF:Rco), von Willebrand antigen (vWF:Ag) and ristocetin-induced platelet aggregation (RIPA). Electrophoretic analysis of plasma showed a complete absence of high–molecular weight vWF multimer. The presence of antibody to vWF was detected by enzyme linked immunosorbent assay (ELISA). Treatment with corticosteroids improved SLE symptoms and corrected bleeding diasthesis. Also, the multimeric patterns of vWF became normalised and anti–vWF antibody disappeared. These findings indicated that this patient had SLE associated with AvWS, which was ameliorated by corticosteroid treatment.