Reversible cerebral vasoconstriction syndrome: a comprehensive systematic review.

OBJECTIVE: We aimed to analyze clinical characteristics, treatment patterns, and prognosis of patients with reversible cerebral vasoconstriction syndrome (RCVS). MATERIALS AND METHODS: Two investigators independently searched PubMed and EMBASE, and 191 cases were included in this study. Information regarding demographics, triggering factors, brain imaging findings, treatment modalities, recurrence, and clinical outcome was collected. RESULTS: The mean age of the patients was 39.9 years, and 155 (81.2%) were female. The most common triggering factor for RCVS was an exposure to vasoactive substances (41.4%), followed by pregnancy/postpartum (20.9%), and sexual intercourse (10.5%). Multifocal stenosis (84.0%) and beading shape (82.4%) were the leading abnormal findings on angiography, while cerebral ischemic lesions (47.6%) and cerebral hemorrhage (mainly subarachnoid hemorrhage) (35.1%) were the main findings on brain computed tomography (CT)/magnetic resonance imaging (MRI). Calcium channel blockers (nimodipine/verapamil) were the most commonly used medications (44.5%) in the treatment of RCVS. Multivariate analysis identified that RCVS was precipitated by trauma/surgery/procedure (hazard ratio (HR): 3.29, 95% confidence interval (CI) (1.21-8.88), p=0.019), and presence of aphasia/neglect/apraxia during the acute phase of the disease (HR: 3.83, 95% CI (1.33-11.05), p=0.013) were found to be the two independent risk factors for residual neurological deficit after RCVS. CONCLUSIONS: In our systematic review, vasoactive substances were the most frequent triggers for RCVS, which was most commonly accompanied by angiographic findings of multifocal stenotic lesions. Patients with RCVS precipitated by trauma or surgical procedures and those with focal cortical deficits had a higher risk of residual neurological deficits, and these patients should closely be monitored.

Evolution and persistence of resistance-associated substitutions of hepatitis C virus after direct-acting antiviral treatment failures.

Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all-oral direct-acting antiviral (DAA) therapy for the genotype 1b HCV-infected patients. In this study, we investigated how resistance-associated substitutions (RASs) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS5A and NS3 revealed typical RASs after treatment failures. Interestingly, the RASs of NS3 reverted to the wild-type amino acid within 1 year after treatment failures. However, the RASs of NS5A were stable and did not change. The effect of NS5A and NS3 RASs on viral RNA replication was assessed after mutagenic substitution in the genotype 1b HCV RNA. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS at NS5A Y93 affected both viral RNA replication and virus production. Finally, the effect of trans-complementation of NS5A was demonstrated in our co-transfection experiments and these results suggest that such a trans-complementation effect of NS5A may help maintain the NS5A RASs for a long time even after cessation of the DAA treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RASs.

Predictors of failure to detect early hepatocellular carcinoma in patients with chronic hepatitis B who received regular surveillance.

BACKGROUND: A proportion of chronic hepatitis B (CHB) patients are diagnosed with advanced hepatocellular carcinoma (HCC) despite regular surveillance. AIMS: To determine predictors for HCC detection failure in CHB patients who underwent regular surveillance. METHODS: CHB patients with well-preserved liver function, who underwent ultrasonography and alpha-foetoprotein (AFP) analysis every 6 months, were enrolled. Cox regression analysis was used to identify predictors for detection failure, defined as HCC initially diagnosed at Barcelona Clinic Liver Cancer (BCLC) stage B or C. RESULTS: Of the 4590 CHB patients (mean age, 52.1 years; men, 61.6%), 169 patients were diagnosed with HCC (3.68%) and 35 (20.7%) HCC patients were initially diagnosed with HCC BCLC stage B or C. The cumulative incidence of HCC detection failure was 0.2% at year 1 and 1.3% at year 5. Multivariate analyses indicated that cirrhosis (hazard ratio [HR], 3.078; 95% CI, 1.389-6.821; P = 0.006), AFP levels ≥9 ng/mL (HR, 5.235; 95% CI, 2.307-11.957; P = 0.010), and diabetes mellitus (HR, 3.336; 95% CI, 1.341-8.296; P = 0.010) were independent predictors of HCC detection failure. Another model that incorporated liver stiffness (LS) values identified LS values ≥11.7 kPa (HR, 11.045; 95% CI, 2.066-59.037; P = 0.005) and AFP levels ≥9 ng/mL (HR, 4.802; 95% CI, 1.613-14.297; P = 0.005) as predictors of detection failure. CONCLUSIONS: In CHB patients undergoing regular surveillance with ultrasonography and alpha-foetoprotein (AFP) analysis every 6 months, the HCC detection failure rate was not high (0.8% per person; 0.1% per test). However, careful attention should be paid in patients with advanced liver fibrosis (clinical cirrhosis or LS value >11.7 kPa), high AFP levels, or diabetes mellitus, who are prone to surveillance failure.

Impact of controlled attenuation parameter on detecting fibrosis using liver stiffness measurement.

BACKGROUND: Liver fibrosis is often accompanied by steatosis, particularly in patients with non-alcoholic fatty liver disease (NAFLD), and its non-invasive characterisation is of utmost importance. Vibration-controlled transient elastography is the non-invasive method of choice; however, recent research suggests that steatosis may influence its diagnostic performance. Controlled Attenuation Parameter (CAP) added to transient elastography enables simultaneous assessment of steatosis and fibrosis. AIM: To determine how to use CAP in interpreting liver stiffness measurements. METHODS: This is a secondary analysis of data from an individual patient data meta-analysis on CAP. The main exclusion criteria for the current analysis were unknown aetiology, unreliable elastography measurement and data already used for the same research question. Aetiology-specific liver stiffness measurement cut-offs were determined and used to estimate positive and negative predictive values (PPV/NPV) with logistic regression as functions of CAP. RESULTS: Two thousand and fifty eight patients fulfilled the inclusion criteria (37% women, 18% NAFLD/NASH, 42% HBV, 40% HCV, 51% significant fibrosis ≥ F2). Youden optimised cut-offs were only sufficient for ruling out cirrhosis (NPV of 98%). With sensitivity and specificity-optimised cut-offs, NPV for ruling out significant fibrosis was moderate (70%) and could be improved slightly through consideration of CAP. PPV for significant fibrosis and cirrhosis were 68% and 55% respectively, despite specificity-optimised cut-offs for cirrhosis. CONCLUSIONS: Liver stiffness measurement values below aetiology-specific cut-offs are very useful for ruling out cirrhosis, and to a lesser extent for ruling out significant fibrosis. In the case of the latter, Controlled Attenuation Parameter can improve interpretation slightly. Even if cut-offs are very high, liver stiffness measurements are not very reliable for ruling in fibrosis or cirrhosis.

Catheter probe endoscopic ultrasonography by using cold lubricating jelly-filled method for esophageal subepithelial tumors.

Catheter probe endoscopic ultrasonography (C-EUS) by ultrasonographic jelly-filled method has been used to evaluate esophageal subepithelial tumors (SETs). Ultrasonographic jelly is safe on the skin, but its internal safety has not been demonstrated. The jelly stored at room temperature is easily injected into the esophagus through the instrument channel of the endoscope. However, using jelly stored at room temperature remains problematic because the jelly is drained rapidly. We used cold lubricating jelly and an intravenous extension tube to resolve these problems. In this study, we evaluated the safety and efficacy of cold lubricating jelly-filled method. The medical records of patients who underwent C-EUS by using water or cold lubricating jelly-filled method for esophageal SETs from March 2013 to September 2016 in Gangneung Asan hospital were reviewed. Clinical characteristics and EUS findings were evaluated retrospectively. Image quality and procedure time between water and cold lubricating jelly-filled method were compared retrospectively. This study included 138 patients (74 males, 64 females) with esophageal SET with a mean age of 57.1 ± 11.1 years. Thirty-four patients had lesions in the upper esophagus, 58 patients had lesions in the middle esophagus, and 46 patients had lesions in the lower esophagus. The EUS diagnoses were leiomyoma (82.6%), hemangioma (4.3%), extrinsic compressive lesion (3.6%), granulosa cell tumor (2.9%), ectopic calcification (1.4%), cyst (1.4%), lipoma (0.7%), varix (0.7%), and inconclusive lesion (2.2%). The mean image score in the cold lubricating jelly filled-method group was higher than that in the water-filled method group (3.2 ± 0.7 vs. 2.8 ± 0.7, P = 0.002). The procedure time in the cold lubricating jelly filled-method group was shorter than that in the water-filled method group (10 minutes 27 seconds ± 4 minutes 22 seconds versus 13 minutes 20 seconds ± 6 minutes 20 seconds, P = 0.045). No procedure-related complication was observed. C-EUS using the cold lubricating jelly-filled method seems to provide better image quality and shorter procedure time compared with C-EUS using the water-filled method.

Polycystic ovary syndrome with hyperandrogenism as a risk factor for non-obese non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with polycystic ovary syndrome (PCOS). However, most studies investigated the prevalence of NAFLD in obese PCOS patients. AIM: To compare the prevalence of non-obese NAFLD in women with or without PCOS, and to assess an independent association between PCOS and NAFLD in a non-obese Asian cohort. METHODS: This was a case-control study using a prospective PCOS cohort. After subjects with other potential causes of chronic liver disease were excluded, 275 non-obese women with PCOS and 892 non-obese controls were enrolled. NAFLD was determined by hepatic ultrasonography. Main outcomes were the prevalence of NAFLD on hepatic ultrasonography between non-obese women with or without PCOS, and an independent association between non-obese NAFLD and PCOS. RESULTS: Non-obese women with PCOS had a significantly higher prevalence of NAFLD than those without PCOS (5.5% vs. 2.8%, P = 0.027). PCOS was associated with non-obese NAFLD (odds ratio: 2.62, 95% confidence intervals: 1.25-5.48) after adjustment for age and body mass index (BMI). In women with PCOS, the level of androgenicity represented by free testosterone or free androgen index was associated with NAFLD after adjustment for age, BMI, lipid profile, insulin resistance or glycaemic status. CONCLUSIONS: Non-obese NAFLD is more prevalent in women with polycystic ovary syndrome than in those without. In non-obese patients with polycystic ovary syndrome, hyperandrogenemia may be an independent risk factor for non-obese NAFLD.

A risk-adapted approach using US features and FNA results in the management of thyroid incidentalomas identified by 18F-FDG PET.

PURPOSE: To assess the risk of malignancy of thyroid incidentalomas found on 18F-FDG PET/CT by US features and cytologic results, and to evaluate the clinical usage of a combination of US features and cytology for post-FNA management of thyroid incidentalomas on 18F-FDG PET/CT. MATERIALS AND METHODS: From September 2006 to December 2008, 132 patients with 134 thyroid incidentalomas detected on 18F-FDG PET/CT who had undergone US and US-FNA were included in this study. We evaluated the malignancy rate of thyroid incidentalomas in different subgroups subdivided by US features and US-FNA cytology results. Several variables were compared between the benign and malignant group. RESULTS: The risk of malignancy was 58.2 % (78/132) in thyroid incidentalomas on 18F-FDG PET/CT. Age, gender, and tumor size were not significantly different between the malignant and benign group.  Malignancy rate of thyroid incidentalomas was significantly higher in the suspicious malignant (88.9 %) than in the probably benign group (11.3 %) on US (p < 0.001). Malignancy rates were high in thyroid nodules with "malignancy", "suspicious for malignancy", or "follicular neoplasm" on cytologic results, regardless of US features. However, malignancy rates of thyroid incidentalomas with "unsatisfactory" or "benign" results on cytology were higher in the suspicious malignant (75 %, 12.5 %, respectively) than in the probably benign (0 %) group on US.  CONCLUSIONS: This study demonstrated that the risk of malignancy was high in thyroid incidentalomas on 18F-FDG PET/CT even without suspicious US features. However, there was no malignancy in nodules with no suspicious US features and benign cytology. Based on these results, we concluded that US may not replace FNA in the diagnosis of PET incidentalomas, and that a follow-up may be considered of thyroid incidentalomas with benign cytology and no suspicious US features.

Association of high body mass index with decreased treatment response to combination therapy in recent-onset rheumatoid arthritis patients.

OBJECTIVE: To assess the association between high body mass index (BMI) and treatment response in recent-onset rheumatoid arthritis. METHODS: In the Behandelstrategieën voor Reumatoide Artritis (Treatment Strategies for Rheumatoid Arthritis) study, 508 patients were randomized to initial monotherapy or combination therapy with prednisone or infliximab (IFX). The response to Disease Activity Score (DAS) ≤2.4-steered treatment (first dose and after 1 year) was compared between patients with a BMI <25 kg/m(2) and ≥25 kg/m(2) , using relative risk (RR) regression analyses. DAS, components of DAS, and functional ability during the first year were compared using linear mixed models. RESULTS: High BMI was independently associated with failure to achieve a DAS ≤2.4 on initial therapy (RR 1.20 [95% confidence interval (95% CI) 1.05, 1.37]). The effect for combination therapy with prednisone was RR 1.55 (95% CI 1.06, 2.28) and for combination therapy with IFX 1.42 (95% CI 0.98, 2.06). The RRs for failure after 1 year were 1.46 (95% CI 0.75, 2.83) and 2.20 (95% CI 0.99, 4.92), respectively. High BMI was also associated with failure on delayed combination therapy with IFX, after adjustment for selection bias related to previous failure on disease-modifying antirheumatic drugs. No significant association was observed in the initial monotherapy groups. In the first year, patients with a high BMI had higher DAS and worse functional ability, with more tender joints and a higher visual analog scale global health, but not more swollen joints and similar systemic inflammation. CONCLUSION: High BMI was independently associated with failure to achieve low DAS on initial combination therapy with prednisone and on initial and delayed treatment with IFX. Patients with a high BMI experienced more pain, but not more swelling or systemic inflammation.

Proposed mechanism in the change of cellular composition in the outer medullary collecting duct during potassium homeostasis.

Potassium depletion (K⁺-D) induces hypertrophy and hyperplasia of collecting duct cells, and potassium repletion (K⁺-R) induces regression of these changes. The purpose of this study was to examine the time courses of the changes in cellular composition, the origin of intercalated cells (ICs) and the mechanism responsible for these changes. SD rats received K⁺-depleted diets for 1, 7, or 14 days. After K⁺-D for 14 days some of the rats received normal diets for 1, 3, 5, or 7 days. In the inner stripe of the outer medulla, K⁺-D increased significantly the number and proportion of H⁺-ATPase-positive ICs, but decreased the proportion of H⁺-ATPase-negative principal cells (PCs). However, proliferation was limited to H⁺-ATPase-negative PCs. During K⁺-R, the cellular composition was recovered to control level. Apoptosis increased during K⁺-R and exclusively limited in H⁺-ATPase-negative PCs. Double immunolabeling with antibodies to PC and IC markers identified both cells negative or positive for all markers during both K⁺-D and K⁺-R. Electron microscopic observation showed that ultrastructure of AE1-positive some cells were similar to AE1-negative some cells during K⁺-R. LC3 protein expression increased significantly and autophagic vacuoles appeared particularly in PCs on days 14 of K⁺-D and in ICs on days 3 of K⁺-R. These results suggest that PCs and ICs may interconvert in response to changes in dietary K+ availability and that autophagic pathways may be involved in the interconversion.

Radiological response predicts survival following transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma.

BACKGROUND: It remains unclear whether initial compact lipiodol uptake after transarterial chemoembolisation (TACE) is associated with improved survival in patients with hepatocellular carcinoma (HCC). AIM: To reveal the clinical relevance of compact lipiodolisation after TACE. METHODS: We studied 490 patients with unresectable HCC who had first been treated with TACE. Compact lipiodolisation was defined as the absence of an arterial enhancing lesion, reflecting complete lipiodol uptake, as assessed by dynamic computed tomography (CT) 1 month after treatment. The rate of initial compact lipiodolisation was analysed according to multiplicity and size of tumour, and survival of patients who achieved compact lipiodolisation was compared to that of patients who did not. RESULTS: Of the 490 patients, 409 (83.5%) were in Child-Pugh class A and 81 (16.5%) in class B. The rate of initial compact lipiodolisation in single HCCs was higher than that in multinodular HCCs (33.7% vs. 14.6%, P < 0.001). Among single HCCs, the rate of compact lipiodolisation in tumours ≤5, 5-10 and >10 cm was 46.6%, 13.6%, and 0% respectively. The 1-, 3- and 5-year survival rates of patients with compact uptake were 92.7%, 70.7% and 52.4% compared to 60.8%, 28.0% and 16.9% in patients with noncompact lipiodolisation. Multivariate analysis revealed that Child-Pugh class, alpha-fetoprotein level, tumour node metastasis stage, portal vein thrombosis and initial compact lipiodolisation were independent predictors of survival. CONCLUSIONS: Initial compact lipiodol uptake after transarterial chemoembolisation is associated with improved survival in patients with unresectable hepatocellular carcinoma. Accordingly, initial complete lipiodolisation should be considered a relevant therapeutic target.

Neutrophil to lymphocyte ratio for preoperative diagnosis of uterine sarcomas: a case-matched comparison.

BACKGROUND: Uterine sarcomas are rare among all uterine malignancies, and frequently misdiagnosed as benign uterine diseases such as leiomyoma and adenomyosis because of lack of feasible tools for the preoperative diagnosis. Although some studies have suggested the role of serum CA-125 levels for the preoperative diagnosis, the efficacy is controversial. Since malignancy is known to be associated with systemic inflammation which leads to hematological alteration, we compared the efficacy for the preoperative diagnosis of uterine sarcomas between the neutrophil to lymphocyte ratio (NLR) and serum CA-125 levels using a case-match comparison. METHODS: From November 2004 to December 2008, 55 patients with carcinosarcoma (n=21), leiomyosarcoma (n=20) and endometrial stromal sarcoma (n=14) were matched to 330 patients with leiomyoma (n=165) and adenomyosis (n=165) in terms of age at diagnosis, body mass index and uterine volume. RESULTS: The receiver operating characteristic curve showed the best cut-off values of the NLR (>or=2.12) and serum CA-125 levels (>or=27.5U/ml) for the preoperative diagnosis of uterine sarcomas, demonstrating that the NLR was more powerful for the preoperative diagnosis of uterine sarcomas than serum CA-125 levels (sensitivity, 74.5% vs. 52.3%; specificity, 70.3% vs. 50.5%; positive predictive value, 29.5% vs. 15.1%; negative predictive value, 94.3% vs. 86.5%; accuracy, 60.6% vs. 49.6%; p<0.05). Furthermore, the NLR reflected recurrence and progression more accurately than serum CA-125 levels in patients with uterine sarcomas. CONCLUSIONS: These findings suggest that the NLR may be more useful than serum CA-125 levels as a cost-effective tool for the preoperative diagnosis in patients with uterine sarcomas.

Factors that affect the diagnostic accuracy of liver fibrosis measurement by Fibroscan in patients with chronic hepatitis B.

BACKGROUND: Interquartile range/median value (IQR/M) of liver stiffness measurement (LSM) is a factor in chronic hepatitis C (CHC) leading to over estimation of fibrosis by Fibroscan. AIM: To investigate factors that affect the accuracy of LSM in chronic hepatitis B (CHB). METHODS: One hundred and ninety-nine patients were enrolled. Only procedures yielding > or =10 valid measurements were considered reliable. Liver fibrosis was evaluated using the Batts and Ludwig system. Liver biopsy (LB) specimens <15 mm were considered ineligible. RESULTS: The mean age (142 men and 57 women) was 40.1 years. A significant discordance (discordance of at least two stages between LB and LSM) was identified in 38 (19.1%) and 47 (23.6%) patients respectively, according to Marcellin et al. and Chan et al.'s cutoff values. In multivariate analyses, BMI and fibrosis stage (F0-2 vs. F3-4) were identified as independent predictors for significant discordance (P = 0.040; hazard ratio [HR], 1.126; 95% confidence interval [CI], 1.005-1.261 and P = 0.036; HR, 0.450; 95% CI, 0.213-0.949 respectively) with Marcellin et al.'s cutoffs, whereas fibrosis stage was the only independent predictor (P = 0.004; HR, 0.300; 95% CI, 0.131-0.685) with Chan's cutoffs. CONCLUSIONS: Success rate and IQR/M were not predictive factors of the accuracy for diagnosing liver fibrosis by Fibroscan in CHB. Fibrosis stage (F0-2) was the only factor to predict significant discordance between LB and LSM.

Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats.

BACKGROUND AND AIMS: Activated hepatic stellate cells (HSCs) but not quiescent HSCs express cyclo-oxygenase-2 (COX-2), suggesting that the COX-2/prostanoid pathway has an active role in hepatic fibrogenesis. However, the role of COX-2 inhibitors in hepatic fibrogenesis remains controversial. The aim of this study was to investigate the antifibrotic effects of celecoxib, a selective COX-2 inhibitor. METHODS: The effects of various COX inhibitors-that is, ibuprofen, celecoxib, NS-398 and DFU, were investigated in activated human HSCs. Then, the antifibrotic effect of celecoxib was evaluated in hepatic fibrosis developed by bile duct ligation (BDL) or peritoneal thioacetamide (TAA) injection in rats. RESULTS: Celecoxib, NS-398 and DFU inhibited platelet-derived growth facor (PDGF)-induced HSC proliferation; however, only celecoxib (> or =50 microM) induced HSC apoptosis. All COX inhibitors completely inhibited prostaglandin E(2) (PGE(2)) and PGI(2) production in HSCs. Separately, PGE(2) and PGI(2) induced cell proliferation and extracellular signal-regulated kinase (ERK) activation in HSCs. All COX inhibitors attenuated ERK activation, but only celecoxib significantly inhibited Akt activation in HSCs. Celecoxib-induced apoptosis was significantly attenuated in HSCs infected with adenovirus containing a constitutive active form of Akt (Ad5myrAkt). Celecoxib had no significant effect on PPARgamma (peroxisome proliferator-activated receptor gamma) expression in HSCs. Celecoxib inhibited type I collagen mRNA and protein production in HSCs. Oral administration of celecoxib (20 mg/kg/day) significantly decreased hepatic collagen deposition and alpha-SMA (alpha-smooth muscle actin) expression in BDL- and TAA-treated rats. Celecoxib treatment significantly decreased mRNA expression of COX-2, alpha-SMA, transforming growth factor beta1 (TGFbeta1) and collagen alpha1(I) in both models. CONCLUSIONS: Celecoxib shows a proapoptotic effect on HSCs through Akt inactivation and shows antifibrogenic effects in BDL- and TAA-treated rats, suggesting celecoxib as a novel antifibrotic agent of hepatic fibrosis.

High prevalence of significant histology in asymptomatic chronic hepatitis B patients with genotype C and high serum HBV DNA levels.

Current treatment guidelines suggest that antiviral therapy be considered for chronic hepatitis B (CHB) patients with high viral load if a biopsy shows significant liver disease despite alanine aminotransferase (ALT) levels two times or less than the upper limit of normal (ULN). We evaluated the histological findings in CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels. Between January 2003 and June 2006, 105 consecutive treatment-naive patients with CHB who underwent ultrasonography-guided percutaneous liver biopsy, had detectable serum HBV DNA (>10(5) copies/mL) in a direct hybridization assay and normal or slightly elevated serum ALT levels (≤2 × ULN) for at least 12 months were included in a prospective study. Histological assessment was based on the METAVIR scoring system. Significant histology was defined as fibrosis stage ≥F2 or necroinflammation grade ≥A2. Among the 105 CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels for at least 12 months, significant fibrosis (F2-F4 fibrosis) was observed in 63 patients (60.0%) and the actual significant histology was found in 65 patients (61.9%). On multivariate analysis, serum ALT levels and age at which they entered the study were independent factors associated with significant histology. Odds ratios for significant histology increased progressively according to serum ALT levels and age. In conclusion, a large proportion of CHB patients with genotype C, high viral load and ALT ≤2 × ULN had significant liver disease on liver biopsy and should be considered for antiviral therapy.

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial.

OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis.

OBJECTIVES: We examined the effects of four different treatment strategies on bone mineral density (BMD) in patients with recently diagnosed, active rheumatoid arthritis (RA) and the influence of disease-related and demographic factors on BMD loss after 1 year of follow-up in the BeSt trial. METHODS: BMD measurements of the lumbar spine and total hip were performed in 342 patients with recent onset RA at baseline and after 1 year. Multivariable regression analyses were performed to determine independent associations between disease and demographic parameters and BMD loss after 1 year. RESULTS: Median BMD loss after 1 year was 0.8% and 1.0% of baseline in the spine and the hip, respectively. No significant differences between the treatment groups, including corticosteroids and the anti-tumour necrosis factor-alpha infliximab, were observed with regard to BMD loss after 1 year of treatment. Joint damage at baseline and joint damage progression according to the Sharp-van der Heijde score were independently associated with more BMD loss after 1 year. The use of bisphosphonates independently protected against BMD loss. CONCLUSIONS: After 1 year of follow-up in the BeSt study, we did not find differences in BMD loss between the four treatment strategies, including high doses of corticosteroids and anti-tumour necrosis factor-alpha. Joint damage and joint damage progression are associated with high BMD loss, which emphasises that BMD loss and erosive RA have common pathways in their pathogenesis.

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial.

OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

Transduction of human catalase mediated by an HIV-1 TAT protein basic domain and arginine-rich peptides into mammalian cells.

Antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) have been considered to have a beneficial effect against various diseases mediated by reactive oxygen species (ROS). Although a variety of modified recombinant antioxidant enzymes have been generated to protect against the oxidative stresses, the lack of their transduction ability into cells resulted in limited ability to detoxify intracellular ROS. To render the catalase enzyme capable of detoxifying intracellular ROS when added extracellularly, cell-permeable recombinant catalase proteins were generated. A human liver catalase gene was cloned and fused with a gene fragment encoding the HIV-1 Tat protein transduction domain (RKKRRQRRR) and arginine-rich peptides (RRRRRRRRR) in a bacterial expression vector to produce genetic in-frame Tat-CAT and 9Arg-CAT fusion proteins, respectively. The expressed and purified fusion proteins can be transduced into mammalian cells (HeLa and PC12 cells) in a time- and dose-dependent manner when added exogenously in culture medium, and transduced fusion proteins were enzymatically active and stable for 60 h. When exposed to H(2)O(2), the viability of HeLa cells transduced with Tat-CAT or 9Arg-CAT fusion proteins was significantly increased. In combination with transduced SOD, transduced catalase also resulted in a cooperative increase in cell viability when the cells were treated with paraquat, an intracellular antioxide anion generator. We then evaluated the ability of the catalase fusion proteins to transduce into animal skin. This analysis showed that Tat-CAT and 9Arg-CAT fusion proteins efficiently penetrated the epidermis as well as the dermis of the subcutaneous layer when sprayed on animal skin, as judged by immunohistochemistry and specific enzyme activities. These results suggest that Tat-CAT and 9Arg-CAT fusion proteins can be used in protein therapy for various disorders related to this antioxidant enzyme.