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Introduction: Patients with rheumatoid arthritis (RA) may have an increased malignancy risk versus the general population, potentially elevated by biological disease-modifying antirheumatic drug (bDMARD) use. Using patient registry data, we determined malignancy risk, stratified by bDMARD use, among Japanese patients with RA versus the Japanese general population and investigated whether bDMARD use is a time-dependent risk factor for the development of malignancy. Methods: Patients aged ≥ 18 years with ≥ 2 data entries of RA in the IORRA (Institute of Rheumatology, Rheumatoid Arthritis) patient registry, enrolled from January 2013–December 2018, were identified (‘All RA’ cohort). Patients were stratified into bDMARD (≥ 1 bDMARD received) or non-bDMARD (no history of bDMARDs) sub-cohorts. Malignancy incidence rates and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) versus the Japanese general population were calculated. Risk of RA medication use was analyzed using a time-dependent Cox proportional hazards model, after adjusting for covariates. Results: A total of 8020 patients were identified for the All RA cohort; 2187 and 5833 for the bDMARD and non-bDMARD sub-cohorts, respectively. For all three cohorts, incidence of overall malignancies was similar versus the Japanese general population. Incidence of specific malignancies was also similar, but incidence of lymphoma was higher for all three cohorts (SIRs [95% CIs] 3.72 [2.71–4.93], 5.97 [3.34–9.59], and 2.79 [1.82–4.02], respectively). In the bDMARD sub-cohort, no increase in SIRs was observed for other site-specific malignancies. In the All RA cohort, use of methotrexate, tacrolimus, glucocorticoids, non-steroidal anti-inflammatory drugs, and bDMARDs were not associated with the risk of overall malignancy; the hazard ratio (95% CI) was 1.36 (0.96–1.93) for bDMARD use. Increased disease activity was a time-dependent risk factor of overall malignancy with a hazard ratio (95% CI) of 1.35 (1.15–1.59). Conclusions: The use of bDMARDs was not a time-dependent risk factor for malignancy.

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P< 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2008.09.082 Byline: Eiichi Tanaka (a)(b), Frederick Y. Chen (c), Robert Flaumenhaft (d), Gwenda J. Graham (d), Rita G. Laurence (a), John V. Frangioni (a)(e) Abbreviations: CABG, coronary artery bypass grafting; FBS, fetal bovine serum; FDA, US Food and Drug Administration; HEPES, N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid; ICG, indocyanine green; LAD, left anterior descending coronary artery; MB, methylene blue; NIR, near-infrared; QY, quantum yield Abstract: We have developed an image-guided surgical system based on invisible near-infrared fluorescent light. Presently, the only clinically available near-infrared fluorophore is indocyanine green, which fluoresces at approximately 800 nm and is used for coronary angiography. Our objective was to determine whether methylene blue, already US Food and Drug Administration approved for other indications, has useful near-infrared fluorescence properties for image-guided cardiac surgery. Author Affiliation: (a) Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Mass (d) Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Mass (e) Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Mass (b) Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (c) Division of Cardiac Surgery, Brigham and Women's Hospital, Boston, Mass Article History: Received 11 April 2008; Revised 29 July 2008; Accepted 6 September 2008 Article Note: (footnote) Supported by National Institutes of Health grants R01-CA-115296 (to J.V.F.), R01-EB-005805 (to J.V.F.), and R01-HL-063250 (to R.F.) and an Established Investigator Award from the American Heart Association (to R.F.).

Two chemical series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodology involves biochemical screening of a high concentration of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compound. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein–ligand structural information. Furthermore, our optimization effort identified the highly potent and orally available 5,7-isoquinoline 37from the second chemical series. Compound 37showed good efficacy in a mouse collagen-induced arthritis model. The in vivo studies suggest that PKCζ inhibition is a novel target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37has the potential to elucidate the biological consequences of PKCζ inhibition, specifically in terms of therapeutic intervention for RA.

This study aimed to evaluate factors associated with osteoporosis medication use in Japanese patients with rheumatoid arthritis (RA).

Following the onset of rheumatoid arthritis (RA), patients experience a functional decline caused by various joint symptoms which affects their activities of daily living and can lead to reduced work productivity. We evaluated the effect of a 52-week treatment with tocilizumab by subcutaneous injection (TCZ-SC) among biologic-naive Japanese house workers (HWs) and paid workers (PWs) with RA in a real-world clinical practice. This multicenter, observational, prospective study enrolled 377 and 347 RA patients into TCZ-SC and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)-alone groups, respectively. The primary endpoint was the change in percentage of overall work impairment (OWI) among PWs at week 52 assessed using the Work Productivity and Activity Impairment Questionnaire (WPAI). Inverse probability of treatment weighting analyses were used to compare treatments. The Work Functioning Impairment Scale, disease activity, quality of life (QOL) measures, and safety were also assessed. The weighted change in OWI from baseline for PWs was −18.9% (TCZ-SC group) and −19.0% (csDMARDs group) at week 52, without a significant between-group difference (adjusted treatment difference 0.1, 95% confidence interval (CI) −6.3 to 6.5; P= 0.978). Changes in WPAI activity impairment in the overall group (between-group difference −6.4, 95% CI −10.7 to −2.2; P= 0.003) and HWs (−9.5, 95% CI − 16.0 to −2.9; P= 0.005) were significantly better with TCZ-SC than with csDMARDs at week 52. TCZ-SC-treated HWs showed significant improvement in all QOL assessments (Frenchay Activities Index, EuroQol 5 Dimension (EQ-5D), Japanese Health Assessment Questionnaire Disability Index (HAQ-DI), and 6-item Kessler scale (K6)) at week 52; PWs did not show any between-group differences for these QOL measures. Disease activity (Disease Activity Score 28-erythrocyte sedimentation rate, Clinical Disease Activity Index, and Simplified Disease Activity Index) and QOL measures (EQ-5D, HAQ-DI, and K6) improved over time in the overall group. No new safety concerns were raised with TCZ-SC. Despite the lack of differences in OWI between groups at week 52, the overall group (particularly HWs) receiving TCZ-SC in addition to csDMARDs showed significant improvements in activity impairment, disease activity, and QOL versus those receiving csDMARDs alone. This study may promote the evaluation of work productivity improvements in HWs and PWs by RA treatment.

Objective.To evaluate longterm functional outcomes in rheumatoid arthritis (RA) based on the number of times that the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) or the 28-joint Disease Activity Score (DAS28) remission criteria were fulfilled.Methods.Patients with RA who participated in all 6 data collections in an observational cohort from 2008 to 2010 and who fulfilled the DAS28 remission criteria at baseline were studied. Patients were classified by the number of times they fulfilled the ACR/EULAR [Boolean trial, Boolean practice, Simplified Disease Activity Index (SDAI), or Clinical Disease Activity Index (CDAI)] or DAS28 remission criteria at each collection. The OR for the Japanese version of the Health Assessment Questionnaire (J-HAQ) progression, based on the number of times each set of remission criteria was fulfilled, were calculated by logistic regression.Results.A total of 915 patients were studied. The OR (95% CI) for J-HAQ progression were 0.54 (0.33–0.87), 0.55 (0.33–0.92), 0.48 (0.28–0.82), 0.29 (0.16–0.51), 0.24 (0.13–0.47), and 0.07 (0.03–0.15) for those fulfilling the Boolean trial remission from 1 to 6 times. This tendency was also observed for the other 4 criteria. The OR (95% CI) for J-HAQ progression in patients who achieved remission at all 6 data collections were 0.07 (0.03–0.14) for the Boolean practice, 0.10 (0.05–0.20) for the SDAI, and 0.07 (0.04–0.15) for the CDAI, whereas 0.15 (0.08–0.29) for the DAS28.Conclusion.Continual fulfillment of any remission criteria was strongly effective in preventing patients from progression of functional disability; however, the ACR/EULAR criteria appear to be preferable.

Background: Infection is one of the primary concerns during treatment for rheumatoid arthritis (RA) in elderly patients. However, infection risk of patients with RA receiving targeted therapy (TT) including biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKIs) in elderly patients are scarce. The aim of this study was to compare the risk of hospitalized infection (HI) with TT versus methotrexate (MTX) therapy among young, elderly, and older elderly patients with RA. Methods: Using Japanese claims data, patients satisfying the following criteria were enrolled: (1) ≥ one ICD10 code for RA; (2) ≥ one prescription of MTX or TT (bDMARDs and JAKIs) between April 2008 and September 2018; and (3) ≥16 years old. We calculated the incidence rate (IR) of HI per 100 patient-years in the young, elderly, and older elderly groups (those aged 16–64, 65–74, and ≥75 years, respectively) and the IR ratio (TT vs. MTX) of HI. A logistic regression model was used to estimate the associations between HI and TT versus MTX in each group. Results: The overall IR of HI per 100 patient-years (95% confidence interval) was 3.2 [2.9–3.5], 5.0 [4.6–5.4], and 10.1 [9.5–10.9] in the young, elderly, and older elderly groups, respectively. Concomitant use of MTX or immunosuppressive DMARDs with TT was less frequent in the elderly and older elderly groups. The adjusted odds ratio of TT vs. MTX for HI was 1.3 (1.0–1.7; p= 0.021), 0.79 (0.61–1.0; p= 0.084), and 0.73 (0.56–0.94; p= 0.015) in the young, elderly, and older elderly groups, respectively. Conclusion: The overall IR of HI was increased with age. The risk of HI under TT compared to MTX was not elevated in elderly and older elderly patients after adjusting for patients’ characteristics and concomitant treatments.

AbstractAs clean and renewable energy, Photovoltaic (PV) systems have been developed quickly nowadays. However, high penetration of PVs would cause overvoltage problem. This paper proposes a cooperative real-time overvoltage prevention control, which is managed by a community energy management system (CEMS). The main idea is to suppress the overvoltage by managing the operation schedule of household loads facilitated by the CEMS. The scheduling by CEMS is formulated as a combinatorial nonlinear time-series scheduling optimization problem in which the profit of the whole community is maximized. A fast heuristic search method called local search method is developed for the purpose of real time control. To validate the proposed method, a simulation of one day schedule is carried out on a 20-customers distribution system model.

Objective.It has been reported that organizing pneumonia (OP) develops when patients with rheumatoid arthritis (RA) are treated with biologic disease-modifying antirheumatic drugs (bDMARD). However, the clinical characteristics and pathophysiology of OP in RA remain unknown in patients treated with bDMARD. We investigated the clinical characteristics and cytokine profiles of patients with RA-OP treated with bDMARD or conventional synthetic DMARD (csDMARD).Methods.Twenty-four patients with RA who had developed OP were enrolled. These patients included 12 treated with bDMARD (bDMARD-OP subset) and 12 treated with csDMARD (csDMARD-OP subset). We compared the clinical characteristics and cytokine profiles between the patients with OP (OP subset, n = 24) and non-OP patients (non-OP subset, n = 29).Results.There was no significant difference in clinical characteristics between the OP subset and the non-OP subset. Four patients developed OP within 2 months of bDMARD administration. In the other 8 patients, OP developed more than 1 year after the initiation of bDMARD. OP improved with corticosteroid treatment in all bDMARD-OP patients. After OP improved, bDMARD were readministered in 6 patients, and no OP recurrence was observed in any of these patients. Our multivariate analysis revealed that serum levels of interferon-α (IFN-α), interleukin (IL)-1β, IL-6, IL-8, and interferon-γ–inducible protein 10 were significantly associated with the development of OP, although these cytokines tended to be lower in the bDMARD-OP subset than in the csDMARD-OP subset.Conclusion.OP is unlikely to be fatal in patients treated with bDMARD or csDMARD. IFN-α and proinflammatory cytokines are associated with the pathophysiology of OP in RA.

Comparisons of data from different registries can be helpful in understanding variations in many aspects of rheumatoid arthritis (RA). The study aim was to assess and improve the comparability of demographic, clinical, and comorbidity data from 5 international RA registries. Using predefined definitions, 2 subsets of patients (main cohort and subcohort) from 5 international observational registries (Consortium of Rheumatology Researchers of North America Registry [CORRONA], the Swedish Rheumatology Quality of Care Register [SRR], the Norfolk Arthritis Register [NOAR], the Institute of Rheumatology Rheumatoid Arthritis cohort [IORRA], and CORRONA International) were evaluated and compared. Patients ages >18 years with RA, and present in or recruited to the registry from January 1, 2000, were included in the main cohort. Patients from the main cohort with positive rheumatoid factor and/or erosive RA who had received ≥1 synthetic disease‐modifying antirheumatic drug (DMARD), and switched to or added another DMARD, were included in the subcohort at time of treatment switch. Age and sex distributions were fairly similar across the registries. The percentage of patients with a high Disease Activity Score in 28 joints score varied between main cohorts (17.5% IORRA, 18.9% CORRONA, 24.7% NOAR, 27.7% CORRONA International, and 36.8% SRR), with IORRA, CORRONA, and CORRONA International including more prevalent cases of RA; the differences were smaller for the subcohort. Prevalence of comorbidities varied across registries (e.g., coronary artery disease ranged from 1.5% in IORRA to 7.9% in SRR), partly due to the way comorbidity data were captured and general cultural differences; the pattern was similar for the subcohorts. Despite different inclusion criteria for the individual RA registries, it is possible to improve the comparability and interpretability of differences across RA registries by applying well‐defined cohort definitions.

Objective.To analyze sex difference in the effect of smoking on remission proportions in patients with rheumatoid arthritis (RA).Methods.Subjects were Japanese patients with RA who participated in the IORRA survey conducted in April 2011 and reported smoking status. Clinical characteristics, treatment status, and the percentages achieving remission were compared between subjects stratified by sex and smoking status. To confirm the differential effects of sex and smoking status on remission, we used multivariate logistic regression models with the dependent variable as 28-joint Disease Activity Score (DAS28) remission.Results.Among 810 men and 4206 women, 162 (20.0%) and 3173 (75.4%), respectively, were never smokers; 208 (25.7%) and 314 (7.5%), respectively, were current smokers. In men, never smokers tended to have higher remission proportions than past and current smokers. In contrast, smoking status seemed not to affect remission in women. Except for lower corticosteroid dose in male never smokers, no significant differences were observed in comparing treatment status. By multivariate analyses, male past and current smokers were negatively associated with DAS28-erythrocyte sedimentation rate remission compared to male never smokers [OR 0.66 and 0.61, 95% CI (0.44–0.98) and (0.39–0.96), respectively]. However, female past and current smokers were not associated with remission compared to female never smokers [OR 1.04 and 1.19, 95% CI (0.86–1.25) and (0.91–1.54), respectively].Conclusion.We demonstrated that the effect of smoking on remission proportions differed between men and women. Our findings suggest that both sex and smoking status are important considerations when planning a treatment strategy for patients with RA.

Recently, the usefulness of the prone position for thoracoscopic esophagectomy has been demonstrated. Thoracoscopic resection of an esophageal submucosal tumor using a prone position also offers advantages over a lateral decubitus position. We describe 2 cases operated on using the prone position for the resection of esophageal submucosal tumor. Case 1 was a 35-year-old man, who was diagnosed with a 50×20 mm leiomyoma in the middle thoracic esophagus, and underwent right thoracoscopic tumor enucleation. Case 2 was a 61-year-old female, who had 45×30 mm esophageal schwannoma in the lower thoracic esophagus with symptoms of dysphagia, and underwent left thoracoscopic tumor enucleation. No complication was observed in both cases. Thoracoscopic esophageal submucosal resection with prone position may add the merits to conventional decubitus position, such as superior visualization, and less bleeding. The side of incision should be determined according to the location of the tumor and anatomic rationality.

A high-pressure sample holder made entirely of titanium and a titanium alloy was constructed for small-angle X-ray scattering (SAXS) measurement of ionic liquids pressurized with CO2. It is designed to vary the path length precisely and perform stable operation at high temperature and pressure, while retaining a constant path length. An in situbeam-monitoring detector for the transmitted X-rays was redesigned and used. SAXS experiments were carried out for an imidazolium-based ionic liquid, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl) amide, pressurized and saturated with CO2. Zero angle scattering intensities, $I(0)$, which directly relate to the mesoscale structural fluctuation, are evaluated from the obtained SAXS intensities. Values of $I(0)$ meaningfully change with the CO2solubility. By using the constructed apparatuses, the anomalous behavior of CO2dissolution into ionic liquids is clarified from the viewpoint of the mesoscale structural change of ionic liquids that fluctuated by dissolved CO2. The present system for SAXS measurement is widely applicable to investigations on structural fluctuations of liquids, solutions including phase separated systems, which are the same as the ionic liquids and CO2mixtures, and amorphous solids under extreme conditions.

Abstract: Background: Endoscopic ultrasound (EUS)-guided drainage is widely used to manage pancreatic pseudocysts. Several studies have reported the use of EUS-guided drainage for pancreatic fistula and stasis of pancreatic juice caused by stricture of the pancreatic duct after pancreatic resection. Methods: At the authors’ hospital, 262 patients underwent surgery involving pancreatic resection from April 2005 to March 2010. In 90 of these patients (34%), a grade B or C postoperative pancreatic fistula developed that required additional treatment. The authors performed EUS-guided transmural drainage (EUS-TD) for six patients (2.1%) with a pancreatic fistula or dilation of the main pancreatic duct visible by EUS. Percutaneous drainage was provided for 18 patients (6.8%). The success rates for EUS-TD and percutaneous drainage were compared in a retrospective analysis. Results: In all six cases, EUS-TD was performed successfully without complications. Five of the six patients were successfully treated with only one trial of EUS-TD. The final technical success rate was 100% for both EUS-TD and percutaneous drainage. Both the short- and long-term clinical success rates for EUS-TD were 100% and those for percutaneous drainage were 61.1 and 83%, respectively. The differences in these rates were not significant (short-term success, P = 0.091 vs. long-term success, P = 0.403). However, the time to clinical success was significantly shorter with EUS-TD (5.8 days) than with percutaneous drainage (30.4 days; P = 0.0013) in the current series. Conclusions: The EUS-TD approach appears to be a safe and technically feasible alternative to percutaneous drainage and may be considered as first-line therapy for pancreatic fistulas visible by EUS.

OBJECTIVE: To clarify the influence of individual joint impairment on functional capacity through a retrospective study with a 3-year interval, using a large cohort of Japanese patients with rheumatoid arthritis (RA). METHODS: Subjects included 3457 patients with RA who participated in a large observational cohort study in both April 2004 and April 2007; 43 joints were assessed and classified into 10 joint areas. Impairment of each joint area was scored based on the presence of swelling or tenderness: score 0 (no swelling or tenderness in either joint), score 1 (swelling or tenderness in a unilateral joint), and score 2 (swelling or tenderness in bilateral joints). Score change was defined as the difference between scores from 2004 and 2007. The Japanese validated version of the Health Assessment Questionnaire is the J-HAQ; ΔJ-HAQ score was determined by subtracting J-HAQ score in 2007 from that in 2004. The relationship between score change and ΔJ-HAQ score, and the effect of joint impairment on ΔJ-HAQ score were assessed. RESULTS: Major joint areas that contributed to ΔJ-HAQ score included the wrist (31%), shoulder (21%), knee (13%), and ankle (10%). The shoulder, wrist, knee, and ankle in the worsening group were associated with a J-HAQ score increase of 0.13 to 0.18 compared to the improvement group. CONCLUSION: Our study demonstrated that impairment of the shoulder, wrist, knee, and ankle significantly affects functional capacity in patients with RA. Care of these joints is suggested to be especially important for better functional outcomes.

We investigated daily needle applicator displacement during multifractionated high-dose-rate interstitial brachytherapy (HDR-ISBT) for postoperative recurrent uterine cancer. Eight patients with postoperative recurrent uterine cancer received HDR-ISBT with or without external beam radiotherapy using our unique ambulatory technique. To analyze displacement, we obtained daily computed tomography (CT) images for 122 flexible needle applicators at 21, 45, 69, and 93 hours after implantation. Displacement was defined as the length between the center of gravity of titanium markers and the needle applicator tips along the daily CT axis. For cases in which displacement was not corrected, we also calculated the dose that covered 90% of the clinical target volume (D90(CTV)) using a dose-volume histogram (DVH). Median caudal needle applicator displacement at 21, 45, 69, and 93 hours was 3, 2, 4, and 5 mm, respectively. More than 15 mm displacement was observed for 2% (2 of 122) and 17% (10 of 60) of needle applicators at 21 and 93 hours, respectively. Cases in which dwell positions were not changed to correct the treatment plan, 2 of 8 patients showed more than 10% reduction in D90(CTV) values compared with the initial treatment plan. Correction of dwell positions of the treatment source improves treatment DVH for multifractionated HDR-ISBT.

To expand the indications for high-dose-rate interstitial brachytherapy (HDR-ISBT) for deep-seated pelvic tumors, we investigated the usefulness of Doppler transrectal ultrasonography (TRUS) guidance and virtual planning. The patient was a 36-year-old female. She had right internal iliac lymph node oligometastasis of vaginal cancer 12 months after radical radiotherapy. The tumor could not be found by gray-scale TRUS and physical examination. Virtual planning was performed using computed tomography with template and vaginal cylinder insertion. We uploaded the images to our treatment planning software and reconstructed the contours of the clinical target volume (CTV) and right internal iliac vessel. Virtual needle applicators were plotted using the template holes for virtual planning. At the time of implantation, Doppler TRUS was used to prevent vessel injury by needle applicators. Applicators were implanted in accordance with virtual planning and Doppler TRUS could detect the right iliac vessel. The percentage of CTV covered by the prescribed dose was 99.8%. The minimum dose received by the maximally irradiated 0.1-cc volume for the right internal iliac vessel was 95% prescribed dose. Complete response was achieved, however, radiological findings showed marginal recurrence at 15 months after HDR-ISBT. Post-radiation neuropathy occurred as a late complication four months after treatment; however, the pain was well controlled by medication. We consider that virtual planning and Doppler TRUS are effective methods in cases where it is difficult to detect the tumor by physical examination and gray-scale TRUS, thereby expanding the indications for ISBT.

To improve treatment conformity for prostate cancer, we investigated daily applicator displacement during high-dose-rate interstitial brachytherapy (HDR-ISBT). Thirty patients treated with HDR-ISBT as monotherapy were examined. All patients received a treatment dosage of 49 Gy per 7 fractions over 4 days. For dose administration, we examined 376 flexible applicators (1128 points) using our unique ambulatory implant technique. Using CT images with a 3-mm slice thickness, we calculated the relative coordinates of the titanium markers and the tips of the applicators. We calculated the distance between the center of gravity of the markers and the tips of the catheters, and compared the distances measured on the day of implantation and the second, third, and fourth treatment days. The mean displacement distance for all applicators was 4.3 ± 3.4 mm, 4.6 ± 4.1 mm, and 5.8 ± 4.5 mm at 21, 45, and 69 hours after initial planning CT. We used a 15-mm margin for needle displacement and only 2 points of 2 patients (16 mm and 18 mm at 69 hours, 2/1128 = 0.2%) exceeded this range. Almost patients (87%) showed the largest displacement within the first 21 hours. The relative doses that covered 100% of CTV (D100(CTV)) values compared with the initial treatment plan were reduced to 0.96 ± 0.08, 0.96 ± 0.08 and 0.94 ± 0.1 at 21, 45 and 69 hours. However, the relative D90(CTV) values kept acceptable levels (1.01 ± 0.02, 1.01 ± 0.03 and 1.01 ± 0.03). Cranial margin of 15 mm seems to be effective to keep D90(CTV) level if we do not do corrective action.

This report presents initial experience with imaging-aided high-dose-rate interstitial brachytherapy (HDR-ISBT) for post-operative recurrence of uterine carcinoma. Fourteen patients presenting with post-operative recurrence of uterine carcinoma (nine cervix and five corpus) between July 2005 and October 2008 were enrolled in this study (median follow-up: 37 months, range: 6-59 months). We implanted magnetic resonance imaging (MRI)-compatible plastic applicators using our own ambulatory technique. HDR-ISBT treatment consisted of twice-a-day irradiation of 6 Gy each with at least a six-hour interval to provide the total prescribed dose. Treatment was based on treatment planning-computed tomography with MRI as a reference. Seven patients were treated with a combination of ISBT (median 30 Gy/5 fractions; range: 27-33 Gy) and external beam radiation therapy (EBRT), and the other seven with brachytherapy only (median 54 Gy/9 fractions; range: 48-54 Gy), one of whom had previously received pelvic EBRT. The three-year estimates of local control and overall survival rates were 77.9% (95% confidence interval (CI): 55.8-100%) and 77.1% (95% CI: 54.2-100%), respectively. Two patients, who had received combined treatment with EBRT showed untoward reactions, including a grade 3 subileus and grade 2 constipation. Another patient, who had been treated with ISBT alone, developed grade 2 urinary constriction. Our imaging-aided HDR-ISBT for post-operative recurrence of uterine carcinoma was found to be practical with promising preliminary results.

Gold nanorods with aspect ratios of 2, 4, and 6 were generated by a seed-mediated growth method developed by Jana et al. and improved by Nikoobakht and El-Sayed. Nanorod formation during synthesis was investigated by time-resolved measurements of small-angle X-ray scattering (SAXS) and in situ UV−vis−NIR absorption. A sample holder made entirely of titanium was newly constructed for the simultaneous measurements. Distance distribution functions were calculated from the SAXS profiles, and the growth in nanorod length as a function of reaction time was determined without having to approximate or simplify the actual nanorod shape. Structural anisotropy, which corresponds to aspect ratio of nanorods, was also evaluated from the functions. For formed nanorods with aspect ratios in the range of 2−4, the time dependence of anisotropy shows maxima. In contrast, for formed aspect-ratio 6 nanorods, a maximum is not observed, and anisotropy continuously increases until an early reaction-equilibrium is reached. Growth kinetics for the variation in the aspect ratios of the formed nanorods is evaluated based on the length growth rate and the width growth rate, each considered individually. Finally, structural changes of nanorod end-caps during synthesis are discussed.

Abstract: Background: Laparoscopic pancreatic surgery is rapidly evolving due to improving instrumentation and surgical techniques. The challenges confronting laparoscopic pancreaticoduodenectomy (LPD), however, are its technical difficulty and its appropriateness for oncologic treatment. This study sought to develop a novel technique for LPD in an acute porcine model and to evaluate the safety and feasibility of LPD before clinical trials are undertaken. Methods: The LPD procedure was performed in 10 pigs. Modified Child’s reconstruction was performed intracorporeally. After the animals were killed, anastomotic sites were investigated by laparotomy. Results: All the animals underwent LPD. The median operation time was 5 h, with minimal blood loss. One choledochojejunostomy had a small leak. Conclusions: The study proved LPD to be technically safe and feasible in an acute porcine model. Further studies and technical advances are necessary for transition of this clinical application of LPD to humans.

Extrahepatic bile duct carcinoma occasionally presents with intraepithelial spread for a considerable area around the main tumor. In this study, we compared clinicopathological features of extrahepatic bile duct carcinoma with and without extensive intraepithelial spread (≥20 mm from the main tumor). Out of 117 cases of extrahepatic bile duct carcinoma, 21 (18%) were found to have extensive intraepithelial spread. Those cases were pathologically characterized by a papillary or nodular main tumor, a more differentiated histological grade, less deep invasion, and infrequent portal vein or hepatic invasion in comparison with cases without intraepithelial spread. Areas of intraepithelial spread histologically consisted of low-papillary growth (17 cases, 81%) and completely flat growth (4 cases, 19%) of carcinoma cells. The former histology corresponded to a macroscopic granular mucosa, whereas the latter growth was hardly detected by gross examination. Immunohistochemically, in 16 of 21 cases (76%), at least one of p53, CEA, and MUC1 was expressed in both the main tumor and the spreading area. Interestingly, patients with intraepithelial spread had a better postoperative prognosis than those without intraepithelial spread (P=0.009). However, three patients had anastomotic recurrence 54–130 months after surgery. In conclusion, intraepithelial-spreading bile duct carcinoma is characterized by papillary or nodular main lesions, a more differentiated histological grade, and less invasiveness. The presence of intraepithelial spread was not an indicator of a poor prognosis, but carcinoma in situ at the bile duct stump could cause late anastomotic recurrence after surgery.Modern Pathology (2008) 21, 807–816; doi:10.1038/modpathol.2008.65; published online 18 April 2008

Accident data show that the injury risks to children seated in Child Restraint Systems (CRSs) are higher in side collisions than any other type. To investigate this, it is necessary to understand the occupant responses in various CRSs. While a sled test procedure has been discussed by the International Organisation for Standardisation for evaluating CRS performance, for which full car side impact tests were conducted with a Q3s child dummy seated in a Forward-Facing (FF) CRS, and a CRABI Six-Month-Old (6MO) infant dummy seated in a Rear-Facing (RF) CRS and also placed in car-bed restraint. In FF and RF CRS tests, the chest was loaded by an intruding door and the resulting chest deflection of the Q3s child dummy in the FF CRS was comparable with the Injury Assessment Reference Value (IARV). In tests with the FF and RF CRSs, the dummy heads were contained within the CRS shell during the entire impact event; and the HICs were small. Although all injury criteria of the CRABI 6MO infant dummy in the car-bed restraint were smaller than the IARVs, a calculated crotch harness force was large.

For prevention of joint destruction in rheumatoid arthritis, optimal management of therapy with disease-modifying antirheumatic drugs is essential. Pharmacogenomic evidence, if reliable, may be incorporated in the treatment of rheumatoid arthritis to achieve a more efficient activity control with minimized adverse events.

OBJECTIVE: To evaluate the association between potential risk factors and incident clinical fractures in Japanese patients with rheumatoid arthritis (RA). METHODS: A total of 1733 female patients with RA over age 50 years were enrolled in a prospective observational cohort study. Participants were followed for 54 months from October 2000 to March 2005, and classified into 4 groups according to incident fracture status since baseline: those without a new fracture; those with a new clinically recognized vertebral fracture; those with an incident nonvertebral fracture at the wrist, hip, humerus, pelvis, or ribs (main nonvertebral fracture); and those with any new nonvertebral fracture. Cox proportional hazard models were used to analyze independent contributions of various risk factors to fracture incidence. RESULTS: During the followup period, 33, 34, and 98 patients developed a vertebral, a main nonvertebral, and any nonvertebral fracture, respectively. The Japanese Health Assessment Questionnaire (J-HAQ) score was associated with relative risks (RR) of 2.42 (95% confidence interval 1.42-4.14), 1.76 (95% CI 1.07-2.89), and 1.73 (95% CI 1.29-2.32) for vertebral, main nonvertebral, and all nonvertebral fractures. The risks of vertebral and any nonvertebral fractures were increased for age over 70 years compared with age in the 50s (RR 3.25, 95% CI 1.19-8.86; and RR 2.22, 95% CI 1.20-4.10, respectively). Clinical variables and medications were associated with a new fracture. CONCLUSION: HAQ, age, history of any prior fracture, and orthopedic surgery for RA appear to be associated with fractures in Japanese women with RA.

We report herein a case of recurrent mucosal cancer of the extrahepatic bile duct, with superficial flat spread, 12 years after operation. A 67-year-old woman had undergone common bile duct (CBD) resection and Roux-en-Y reconstruction. Histologically, the tumor was papillary adenocarcinoma, with superficial flat spread, with no invasive component. The epithelium at the distal margin had been exfoliated, so the absence or presence of any remnant cancerous lesion was unclear. But the superficial flat spread had expanded to within at least 3 mm from the distal margin. About 12 years postoperatively, she was hospitalized with upper abdominal pain, and duodenoscopy demonstrated a tumor in the second portion of the duodenum. Biopsy identified adenocarcinoma. Computed tomography showed a low-density mass between the duodenum and pancreatic head. Pancreatoduodenectomy was performed. Histologically, papillary adenocarcinoma was found within the whole of the intrapancreatic bile duct, and its histological appearance resembled that of the original tumor. Moderately differentiated tubular adenocarcinoma had invaded around the tissue of the intrapancreatic CBD. These findings suggest that remnant intramucosal flat carcinoma within the intrapancreatic bile duct had developed into invasive carcinoma over the course of 12 years. This case suggests that remnant intraepithelial flat carcinoma within the CBD may develop a late local recurrence.We report herein a case of recurrent mucosal cancer of the extrahepatic bile duct, with superficial flat spread, 12 years after operation. A 67-year-old woman had undergone common bile duct (CBD) resection and Roux-en-Y reconstruction. Histologically, the tumor was papillary adenocarcinoma, with superficial flat spread, with no invasive component. The epithelium at the distal margin had been exfoliated, so the absence or presence of any remnant cancerous lesion was unclear. But the superficial flat spread had expanded to within at least 3 mm from the distal margin. About 12 years postoperatively, she was hospitalized with upper abdominal pain, and duodenoscopy demonstrated a tumor in the second portion of the duodenum. Biopsy identified adenocarcinoma. Computed tomography showed a low-density mass between the duodenum and pancreatic head. Pancreatoduodenectomy was performed. Histologically, papillary adenocarcinoma was found within the whole of the intrapancreatic bile duct, and its histological appearance resembled that of the original tumor. Moderately differentiated tubular adenocarcinoma had invaded around the tissue of the intrapancreatic CBD. These findings suggest that remnant intramucosal flat carcinoma within the intrapancreatic bile duct had developed into invasive carcinoma over the course of 12 years. This case suggests that remnant intraepithelial flat carcinoma within the CBD may develop a late local recurrence.

Castleman's disease is an uncommon lymphoproliferative disorder, which occurs most commonly in the mediastinum. Sporadic reports of its occurrence in the hepatoduodenal ligament and other extrathoracic locations have also been documented. Ultimately, Castleman's disease can develop anywhere lymphoid tissue is found, and the preoperative diagnosis is often difficult. We report a case of hyaline vascular-type Castleman's disease in the hepatoduodenal ligament. An asymptomatic 26-year-old woman was admitted to our hospital for further examination of a mass found on ultrasonography. A contrast-enhanced computed tomography scan confirmed a hypervascular mass in the hepatoduodenal ligament, and angiography showed that the mass was receiving its blood supply from various arteries. These findings suggested a diagnosis of Castleman's disease and we removed the tumor without resecting any other organs. Computed tomography and angiography were helpful in establishing a correct preoperative diagnosis, which minimized the magnitude of surgery.Castleman's disease is an uncommon lymphoproliferative disorder, which occurs most commonly in the mediastinum. Sporadic reports of its occurrence in the hepatoduodenal ligament and other extrathoracic locations have also been documented. Ultimately, Castleman's disease can develop anywhere lymphoid tissue is found, and the preoperative diagnosis is often difficult. We report a case of hyaline vascular-type Castleman's disease in the hepatoduodenal ligament. An asymptomatic 26-year-old woman was admitted to our hospital for further examination of a mass found on ultrasonography. A contrast-enhanced computed tomography scan confirmed a hypervascular mass in the hepatoduodenal ligament, and angiography showed that the mass was receiving its blood supply from various arteries. These findings suggested a diagnosis of Castleman's disease and we removed the tumor without resecting any other organs. Computed tomography and angiography were helpful in establishing a correct preoperative diagnosis, which minimized the magnitude of surgery.

To determine the most sensitive scoring method for assessment of rheumatoid arthritis (RA) disease activity using the American College of Rheumatology Core Data Set.The subjects were 4,530 patients with RA (mean age 57.9 years, mean disease duration 12.7 years) who participated in a large observational cohort study of RA patients. The 68 joints assessed were classified into 15 joint areas, and each joint variable was categorized based on the presence or absence of swelling or pain in these areas. Multiple linear regression and analysis of variance were used to evaluate the significance of effects of these 15 joint areas on variables for assessment of RA disease activity such as patient's assessment of pain on a visual analog scale (VAS), patient's and physician's global assessment of disease activity on a VAS, HAQ (Health Assessment Questionnaire), and Japanese HAQ.Although the 3 most frequently affected joints were the wrist, metacarpophalangeal joints, and proximal interphalangeal joints, the 5 joints with the largest contributions to all of the variables assessed for disease activity were the shoulder, elbow, and knee joints, followed by the wrist and ankle joints. The combination of shoulder, elbow, and knee joints accounted for approximately 70% of the contribution to all the variables, while addition of the wrist and ankle joints increased this value to approximately 90%.Scoring for assessment of RA disease activity would be more sensitive if separate joints such as the shoulder, elbow, knee, wrist, and ankle joints were weighted differently.

We report the case of a patient with pancreatic head cancer, whose replaced common hepatic artery (RCHA) arose from the superior mesenteric artery (SMA). We performed preoperative embolization of the RCHA, after which the liver blood flow was well maintained by the left gastric artery. The patient underwent a radical operation involving en bloc resection of the RCHA without any serious complications.

Purpose. To clarify the role of hepatic resection in the surgical treatment of hilar bile duct carcinoma. Methods. Between 1980 and 1997, 68 patients underwent surgery for hilar bile duct carcinoma. The patients were divided into a hepatectomy group ( n = 40) and a nonhepatectomized group ( n = 28) depending on whether they underwent resection of the bile duct confluence in combination with hepatectomy, or alone, respectively. Background data, operative morbidity and mortality, and survival were retrospectively compared between the two groups. Results. There were no significant differences in morbidity and mortality, or in postoperative survival between the two groups (the 5-year survival rates being 20.6% in the hepatectomized group and 7.1% in the nonhepatectomized group; P = 0.0806). However, patients who underwent curative resection had significantly better postoperative survival than those who underwent noncurative resection ( P = 0.048). Hepatectomy provided a significantly better cancer-free margin than bile duct resection alone ( P = 0.0296). Conclusions. Although a countermeasure must be taken to decrease mortality, the introduction of hepatectomy with bile duct resection would provide a better cancer-free surgical margin than bile duct resection alone for hilar bile duct carcinoma. Curative resection contributed to long-term survival in this series.

Purpose Stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries is a radical operation performed for locally advanced cancer of the pancreatic body. However, it is not known whether the collateral pathways that develop immediately from the superior mesenteric artery to the gastroduodenal and hepatic arteries provide sufficient blood flow to support the hepatobiliary system and the stomach. This article examines the ischemic gastropathy that can occur after this procedure and identifies the predisposing conditions. Methods Between 1997 and 2001, nine patients underwent stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries. Concomitant resection of the right gastric artery or gastroduodenal artery was performed due to cancer infiltration in three patients. Results Irregular, shallow, and wide ulcerations thought to be ischemic in origin developed in these three patients, but all the ulcerations healed in 1–2 weeks with antiulcer medication. None of the other six patients had evidence of gastric ischemia. Conclusions Ischemic gastropathy is rare after distal pancreatectomy with celiac axis resection alone; however, division of additional arteries supplying the stomach may predispose to ischemic gastropathy.

To develop and validate a self-administered instrument for measuring functional status in Japanese-speaking rheumatoid arthritis patients. We translated the Stanford Health Assessment Questionnaire (HAQ) into Japanese (original HAQ), and then made a tentative Japanese version of the HAQ (J-HAQ) with culturally appropriate modifications of the arising, eating, and reach category questions. The questionnaire was then administered to 3,763 RA patients (82.6% female; mean age 58.0 years; mean onset age 47.4 years; mean disease duration 10.5 years). This instrument showed excellent internal reliability (Cronbach's α = 0.927), with a mean interitem correlation of 0.60. For the arising category question, the J-HAQ asks about arising from a futon in addition to a bed because futons are still common in Japanese culture. Arising from a futon is generally more difficult for disabled individuals than is arising from a bed, so the arising score was higher in the J-HAQ (mean score 0.82) than in the original HAQ (0.48). The average scores for the eating and reach categories were virtually identical for the original HAQ and the J-HAQ, with correlation coefficients of 0.979 and 0.926, respectively. Thus, the overall disability index (average of the scores for all functional areas) was higher in the J-HAQ (0.81) than in the original HAQ (0.76), although the correlation coefficient was high (0.993). The test-retest reliability value (0.92), studied at a 1-week interval, revealed identical disability index scores measured on the 2 occasions. The final version of the J-HAQ is a valid and reliable instrument for measuring functional status in Japanese-speaking RA patients.

This paper presents a row-action maximum likelihood algorithm (RAMLA), in which the relaxation parameter is controlled in such a way that the noise propagation from projection data to the reconstructed image is substantially independent of the access order of the input data (subsets) in each cycle of the sub-iterations. The &lquot;subset-dependent&rquot; relaxation parameter λ_k (q) is expressed as λ_k(q) &equal; β₀/(β₀ + q + γkM), where M is the number of angular views, q (0 ≤ q ≤ M − 1) is the access order of the angular view, k is the iteration number and β₀ and γ are constants. The constant β₀ deals with the balance of the noise propagation and the constant γ controls the convergence of iterations. The value of β₀ is determined from the geometrical correlation coefficients among lines of coincidence response. The proposed RAMLA using the subset-dependent (dynamic) relaxation &lquot;dynamic RAMLA (DRAMA)&rquot; provides a reasonable signal-to-noise ratio with a satisfactory spatial resolution by a few iterations in the two-dimensional image reconstruction for PET. Dynamic OS-EM (DOSEM) has also been developed, which allows the use of a larger number of subsets (OS level) M_sub without loss of signal-to-noise ratio as compared to the conventional OS-EM. DRAMA is a special case of DOSEM, where M_sub &equal; M, and it is no more profitable to use DOSEM with a smaller M_sub (&lt;M), because DRAMA provides similar performance with the fastest convergence and smallest computer burden. This paper describes the theory, algorithm and the results of the simulation studies on the performance of DRAMA and DOSEM.

OBJECTIVE: N-acetyltransferase 2 (NAT2) is a key enzyme for the acetylation of sulfasalazine (SSZ). We examine whether there was a correlation between diplotype configurations (combinations of 2 haplotypes for a subject) at the NAT2 gene and the adverse effects of SSZ used for the treatment of rheumatoid arthritis (RA). METHODS: The findings from 144 patients with RA who had been treated with SSZ were collected from our outpatient department and used for a retrospective study. Haplotype analysis was performed by the maximum-likelihood estimation based on the EM algorithm using the obtained polymorphism data. RESULTS: Sixteen patients (11.1%) had experienced adverse effects from SSZ, the most common being allergic reactions including rash and fever. The slow acetylators who had no NAT2*4 haplotype had experienced adverse effects more frequently (62.5%) than the fast acetylators who had at least one NAT2*4 haplotype (8.1%) (p < 0.001, OR 7.73, 95% CI 3.54-16.86). In 25% of the slow acetylators, the adverse effects were so severe that they were hospitalized. CONCLUSION: Genotyping the NAT2 gene followed by estimation of diplotype configuration before administration of SSZ is likely to reduce the frequency of adverse effects in Japanese patients with RA.

Abstract.: Background/Purpose: We report our experience performing wedge resection of the portal bifurcation and transverse suture closure in patients undergoing left hepatectomy and caudate lobectomy plus biliary reconstruction for hepatobiliary cancer. Methods: The procedure was performed in three patients with hilar or intrahepatic cholangiocarcinoma. After confirming that tumor invasion of the portal bifurcation was not circumferential, the portal trunk and the right posterior and right anterior portal branches were isolated and clamped. Wedge resection of the portal bifurcation was performed, taking care to secure a clear surgical margin. The edges of the portal vein were approximated, using guy-sutures in the dorsal and ventral edges and a temporary central guy-suture, and portal reconstruction was carried out using a continuous transverse suture. After unclamping, good portal flow was confirmed by color Doppler ultrasonography. Results: The procedure was completed successfully in all three patients; the average time of portal vein occlusion was 15 min. Two patients had postoperative complications: bile leakage and wound infection, but no patient developed postoperative hepatic failure or died. The three patients are alive without recurrence at 2, 11, and 22 months after the operation. Conclusions: Wedge resection of the portal bifurcation is easier and simpler than using a venous patch or performing segmental resection.

OBJECTIVE: To determine the effect of excessive induction of hepatocyte growth factor (HGF)/c-met signaling in fibroblasts derived from patients with systemic sclerosis (SSc). METHODS: Fibroblasts were obtained from skin of patients with SSc and healthy controls. The 2.4 kb interleukin 1alpha (IL-1alpha) cDNA was subcloned into pcDNA3 expression vector, which was stably transfected into normal fibroblasts by lipofection. HGF production in cultured fibroblasts was measured by ELISA. C-met protein (a receptor for HGF) in cultured fibroblasts was evaluated by immunocytochemistry using polyclonal anti-c-met antibody. Production of procollagen type I was estimated by an ELISA system using antibodies against procollagen type I C-peptide. RESULTS: Cultured skin fibroblasts expressed mRNA and protein of HGF constitutively in both SSc and control cultures. However, HGF production in SSc fibroblasts was significantly higher than in normal fibroblasts. In both SSc and normal fibroblasts, HGF production was dose dependently increased by the addition of recombinant IL-1alpha. Immunocytochemical staining revealed that c-met was spontaneously expressed in SSc fibroblasts, whereas no expression of c-met was detected in normal fibroblasts. C-met mRNA was expressed in normal fibroblasts transfected with the IL-1alpha gene. Addition of recombinant HGF (100 ng/ml) to cultured SSc fibroblasts significantly decreased procollagen type I production. CONCLUSION: High concentration of HGF inhibited collagen production in cultured fibroblasts derived from patients with SSc. Overexpression of HGF/c-met appears to be a biological feedback response to the fibrotic process of SSc, suggesting that the antifibrotic effect of HGF might be used as a novel strategy for treatment of SSc.

We examined two sumo wrestlers who had tackler’s bony spur. In football players, these spurs are secondary to subperiosteal hematoma formation from repeated direct blows by an opponent or from ill-fitting shoulder pads. The initial charge of sumo wrestling is similar to a tackle in American football. Our two patients had had repeated direct blows by opponents on the initial wrestling charge. The tackler’s bony spurs of our two patients were located on the lateral aspect of the humeral shaft just distal to the deltoid insertion, and there was no involvement of the anterior mass of the brachialis muscles or elbow. We consider that tackler’s bony spurs are sometimes, but not often, seen in sumo wrestlers.

OBJECTIVE: To investigate the usefulness of the radiographic scoring method proposed by Rau, et al for evaluation of joint damage in patients with early rheumatoid arthritis (RA). METHODS: Radiographs of hands and feet of 30 prospectively observed patients with early RA were assessed by the Rau method, the Larsen method, and count of erosive joints. The standardized response mean (SRM) was used to estimate the sensitivity to change of each method of assessment. RESULTS: Although the Rau method evaluates only the amount of bony erosion, nearly equivalent radiographic progression was observed with the Rau and the Larsen methods. Radiographic changes in the first year were sensitively identified by all 3 methods (SRM for Rau method 0.83, Larsen method 0.88, and count of erosive joints 0.84). However, in the period from 2 to 6 years after entry into the study, sensitivity to change was maintained with use of the Rau (SRM 1.38) and Larsen (SRM 0.95) methods, but not by count of erosive joints (SRM 0.49). While an apparent ceiling effect was observed after 2 years in count of erosive joints, no ceiling effects were noted for the Rau and Larsen methods. CONCLUSION: Our study showed that the usefulness of the Rau method is equivalent to the Larsen method in clinical assessment of radiographic progression in early RA.

5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFRgene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFRgene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without P<0.05, relative risk (RR) 2.18, 95 confidence interval (CI) 1.17–4.06, while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P<0.05, RR 1.25, 95 CI 1.05–1.49). An estimation of haplotype frequencies showed that there was no 677T–1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C–1298C haplotype were receiving lower doses of MTX than those without (P<0.05, RR 2.14, 95 CI 1.13–4.07), while subjects with 677T–1298A had a higher frequency of side-effects from MTX (P<0.05, RR 1.42, 95 CI 1.11–1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFRgene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.

OBJECTIVE: To clarify the clinical features of systemic lupus erythematosus (SLE) complicated with pulmonary hypertension (PH) and to evaluate the efficacy of immunosuppressive treatment. METHODS: Case records were reviewed for 194 patients with SLE who were admitted to Aoyama Hospital of Tokyo Women's Medical University between 1992 and 1999. There were 12 patients with PH [8 SLE and 4 SLE + systemic sclerosis (SSc) overlap syndrome]. These patients were compared with 59 age and sex matched patients with SLE for clinical characteristics and laboratory findings. The efficacy of treatments for PH was also evaluated. RESULTS: In our cohort of 194 patients with SLE, 6.2% had PH. The plasma thrombin-antithrombin III complex and plasma D-dimer levels were significantly higher in patients with PH compared with those without PH. Eight patients with PH (4 SLE and 4 SLE + SSc) were treated with corticosteroids (CS) +/- cyclophosphamide (CYC). Right ventricular systolic pressure (RVSP) was improved in 7 of 8 patients. In 6 of 7 responders to the therapy, the treatment was started as soon as they were diagnosed with PH. PH relapsed in 2 patients treated with oral CS +/- CS pulse therapy, but their RVSP was decreased again by immunosuppressive treatment. CONCLUSION: CS +/- CYC was effective for PH associated with SLE. Immunosuppressive treatment should be performed during the early stage of PH to improve prognosis.

Purpose: To evaluate tongue hemiatrophy as a late effect of brachytherapy, a new grading system was designed and applied to patients who had received low dose rate (LDR) or high dose rate (HDR) brachytherapy for early tongue cancer.

This paper presents a PET scanner capable of acquiring projection data in three-dimensional (3D) and two-dimensional (2D) modes simultaneously. The scanner has rotating partial slice-septa, and coincidence events are stored as 2D data or as 3D data depending on whether the lines of response are collimated by the septa or not. 68Ge/Ga rod sources can be set on the rotating septa, and a transmission scan for attenuation correction is performed in the 2D mode. The scanner allows simultaneous 3D-emission/2D-transmission scanning or post-injection transmission scanning with little cross-talk. A blank scan for detector normalization is also performed with the rotating rod sources in the 2D mode, from which we can derive the normalizing factors in both modes. The 3D/2D difference method is available for scatter correction, even in a dynamic study where the source distribution is changing. A `summation method' is proposed as a new image reconstruction algorithm, in which the high- and low-frequency components of images are reconstructed from the 3D and 2D data respectively. In this method, most of the scatter contribution in the 3D data is removed by high-pass filtering, not by subtracting estimated scatter distribution, and hence the method is expected to be robust for scatter from outside the axial field of view. Computer simulations revealed that the rotating partial septa offer a single-scatter to true ratio similar to that of the conventional full septa if the depth of the partial septa is properly lengthened, with a small increase in multiple scattering.

Purpose: To investigate the viability of perioperative fractionated HDR brachytherapy for malignant bone and soft tissue tumors, analyzing the influence of surgical margin.

A new method of image reconstruction for single photon emission computed tomography is presented. The method is basically a filtered backprojection with some modifications. The algorithm consists of three steps: normalization of observed projections, modified convolution operation, and weighted backprojection. The weighting function for backprojection is determined to provide perfect attenuation compensation for a uniform attenuation medium and to keep the statistical noise in the reconstructed image low. The relative contributions of two conjugate projections to the image can be controlled by the reconstruction parameters, enabling improvement of the signal-to-noise ratio and spatial resolution at off-center area compared with the conventional averaging method of two conjugate projections. Simulation studies indicated that the method provides a satisfactory image for an extended source of “Tc(μ= 0.15 cm”1) having a diameter of up to approximately 35 cm. A myocardium phantom is adequately reconstructed from a 180 ± 225 angle scan. The effect of nonuniform attenuation medium surrounding the source region can be corrected. This paper presents the mathematical basis of the procedure, the evaluation of the statistical noise, and some illustrative computer simulations.

The image-forming performance of multilayer positron tomographs for extended sources is evaluated analytically. The analysis is simplified by “rotation transform,” by which three-dimensional photon detection problems are solved by two-dimensional treatment. Event rates of singles, unscattered true coincidence, and single- and double-scattered coincidence are formulated for a uniform cylinder phantom as functions of various design parameters. Angle factors for Compton scattering and other parameters used in the evaluation are presented. Scatter components in projections and their effect on the reconstructed images are also evaluated. The scatter component in the reconstructed image depends critically on the detector ring radius, phantom radius, method of attenuation correction, etc. When the detector ring radius is relatively small (40 ± 45 cm in diameter), the scatter/true ratio at the image center of a 20 cm diameter phantom may be larger than the scatter/true ratio in the event rates. Comparison with experimental data obtained with a head positron tomograph, positologica, showed reasonable agreement both in the total coincidence rates and in the scatter components in the images for a cylindrical phantom of 20 cm in diameter.

DNA fragments Vibrio alginolyticuschemovar iophagus, at least 7 kb in length, were ligated to Escherichia coliexpression vectors. Three clones of Escherichia coliHB101 (pLCO‐1, pLCO‐2, pLCO‐3) were obtained by the colony immunoblotting method using anti‐collagenase antibody. In Escherichia coli, all these genes produced collagenase antigens which were detected with Western blotting. The amino acid sequence of chemically purified collagenase fragments was also analyzed. An approximately 2.5 kb DNA fragment of the pLCO‐1 clone was sequenced, and we found that portions of the deduced amino acid sequence were completely identical with the corresponding amino acid sequence of the chemically analyzed fragments. Therefore, it is highly probable that the gene studied in the present experiment is truly a collagenase structural gene.

Optokinetic nystagmus (OKN) and after-nystagmus (OKAN) were investigated in monkeys subjected to conventional and reversed optokinetic stimulation. The decreasing patterns of OKAN slow phase speed (SPS) changed from a straight to a catenary-like pattern with increased stimulus speed. The total duration, however, of the first and second phases remained unchanged. Immediately after a sudden reversal of the stimulus direction, neither OKAN nor OKN was induced; the slow rising portion of OKN SPS became 1.2-1.6 times longer than that of the usual OKN. Since OKN inhibition after stimulation reversal shared similar characteristics with the slow rise of OKN SPS in the light and with the decrease of OKAN SPS in the dark, all of these can be regarded as adaptive processes of the after-nystagmus-producing mechanism.

The effects of correction function on image characteristics were studied experimentally for a positron CT device Positologica. Correction functions were obtained by smoothing the Shepp and Logan function by convolution of Gaussian functions. Signal-to-noise ratio (SNR) and spatial resolution were measured for phantoms and related to the magnitude of smoothing. The relation between SNR and spatial resolution is also discussed. Some suggestions are made to indicate how to select correction functions for clinical images. A flow of data processing for Positologica is described together with an outline of its hardware.