Alterations of ATG4A and LC3B in neurons derived from Alzheimer's disease patients.

We investigated the alterations in autophagy-related molecules in neurons differentiated from induced pluripotent stem cells obtained from patients with Alzheimer's disease (AD). Consistent with our previous microarray data, ATG4A protein was upregulated in the neurons derived from a familial AD patient with an APP-E693Δ mutation who showed accumulation of intracellular amyloid ß peptide (Aß). This upregulation was reversed by inhibiting Aß production, suggesting that the intracellular Aß may be responsible for the upregulation of ATG4A. The LC3B-II/LC3B-I ratio, an index of autophagosome formation, was lower in the neurons derived from the AD patient with APP-E693Δ as well as the neurons derived from other familial and sporadic AD patients. These findings indicate that dysregulation of autophagy-related molecules may accelerate the pathogenesis of AD.

Identification and Characterization of Synaptic Vesicle Membrane Protein VAT-1 Homolog as a New Catechin-Binding Protein.

(-)-Epigallocatechin-3-gallate (EGCg), a major constituent of green tea extract, is well-known to exhibit many beneficial actions for human health by interacting with numerous proteins. In this study we identified synaptic vesicle membrane protein VAT-1 homolog (VAT1) as a novel EGCg-binding protein in human neuroglioma cell extracts using a magnetic pull-down assay and LC-tandem mass spectrometry. We prepared recombinant human VAT1 and analyzed its direct binding to EGCg and its alkylated derivatives using surface plasmon resonance. For EGCg and the derivative NUP-15, we measured an association constant of 0.02-0.85 ×103 M-1s-1 and a dissociation constant of nearly 8 × 10-4 s-1. The affinity Km(affinity) of their binding to VAT1 was in the 10-20 µM range and comparable with that of other EGCg-binding proteins reported previously. Based on the common structure of the compounds, VAT1 appeared to recognize a catechol or pyrogallol moiety around the B-, C- and G-rings of EGCg. Next, we examined whether VAT1 mediates the effects of EGCg and NUP-15 on expression of neprilysin (NEP). Treatments of mock cells with these compounds upregulated NEP, as observed previously, whereas no effect was observed in the VAT1-overexpressing cells, indicating that VAT1 prevented the effects of EGCg or NUP-15 by binding to and inactivating them in the cells overexpressing VAT1. Further investigation is required to determine the biological significance of the VAT1-EGCg interaction.

Current status of the position on labor progress prediction for contemporary pregnant women using Friedman curves: An updated review.

AIM: Prediction of labor progression is important for maternal and fetal health, as improved accuracy can lead to more timely intervention and improved outcomes. This review aims to outline the importance of predicting the progression of spontaneous parturition, detail the various methods employed to enhance this prediction and provide recommendations for future research. METHODS: We searched articles relating to labor progression and systematic review articles on Artificial Inteligence (AI) in childbirth management using PubMed. To supplement, Google Scholar was used to find recent guidelines and related documents. RESULTS: Traditional methods like vaginal examinations, criticized for subjectivity and inaccuracy, are gradually being replaced by ultrasound, considered a more objective and accurate approach. Further advancements have been observed with machine learning and artificial intelligence techniques, which promise to surpass the accuracies of conventional methods. The Friedman curve, developed in 1954, is the standard for assessing labor progress, but its application to Asian women, in particular, remains controversial, and various studies have reported that the actual rate of labor was slower than that indicated by the Friedman curve. CONCLUSION: There is a need to innovate methodologies for predicting delivery tailored to modern pregnant women, especially when they have different genetic and cultural backgrounds than their Western counterparts, such as Asians. Future research should develop predictive models of labor progression that aim to enhance medical intervention and improve the safety and well-being of both mother and child.

"Role-sharing surgery": a new surgical education system that gives beginner surgeons more chances to operate while ensuring the surgical quality of robotic surgery.

It has been pointed out that robotic surgery is more time-consuming than laparoscopic surgery, and a major challenge for the future is educating young surgeons while maintaining the surgical quality. To solve these problems, we report a role-sharing surgery (RSS) approach in which the surgery is divided into several areas and timetabled, with roles shared by several operators. We performed RSS for 19 standard colorectal cancer surgeries. The surgery was completed within + 28 min of the scheduled operation time, and a beginner robotic surgeon (BRS) was able to perform approximately 66% of the total surgery. There were no statistically significant differences in the short-term outcomes between the RSS and conventional surgery groups. Based on these findings, RSS has the potential to be the best practice for educating BRSs in robotic surgery, the use of which is expected to increase steadily in the future.

[A Case of Transverse Colon Cancer with Gastrointestinal Amyloidosis Prevented from Anastomotic Leakage by Multidimensional Approach].

The patient was a 68-year-old woman who was on hemodialysis due to systemic amyloidosis and nephrotic syndrome. Biopsy revealed amyloid deposition in the stomach, duodenum, and colon. A transverse colon tumor was found on a follow- up CT after the aortic dissection surgery. We performed lower gastrointestinal endoscopy and contrast-enhanced CT and diagnosed transverse colon cancer with gastric wall infiltration(cStage Ⅲc). We considered that transverse colon resection was oncologically sufficient. However, due to concurrent gastrointestinal amyloidosis, which increased the risk of anastomotic leakage we performed laparoscopic extended right hemicolectomy to avoid colon-colon anastomosis with partial gastrectomy. Additionally intraoperative indocyanine green(ICG)fluorescence imaging showed that the fluorescence signal in the small intestinal wall was satisfactory, while it was weak in the colon wall. As a result, we suspected of impaired blood flow of colon wall due to an amyloidosis, so we additionally created a loop ileostomy. It is said that gastrointestinal amyloidosis raises the risk of anastomotic leakage. A case of transverse colon cancer complicated by gastrointestinal amyloidosis in which we successfully prevented anastomotic leakage through a multidimensional evaluation and approach is reported, along with a literature review.

Enhancement of Neprilysin Activity by Natural Polyphenolic Compounds and Their Derivatives in Cultured Neuroglioma Cells.

The onset of Alzheimer's disease (AD) is characterized by accumulation of amyloid ß peptide (Aß) in the brain. Neprilysin (NEP) is one of the major Aß-degrading enzymes. Given findings that NEP expression in the brain declines from the early stage of AD before apparent neuronal losses are observed, enhancement of NEP activity and expression may be a preventive and therapeutic strategy relevant to disease onset. We screened for compounds that could enhance the activity and expression of NEP using a polyphenol library previously constructed by our research group and investigated the structure-activity relationships of the identified polyphenols. We found that amentoflavone, apigenin, kaempferol, and chrysin enhanced the activity and expression of NEP, suggesting that chemical structures involving a double bond between positions 2 and 3 in the C ring of flavones are important for NEP enhancement, while catechol or pyrogallol structures, except for the galloyl group of catechins, abolished these effects. Moreover, natural compounds, such as quercetin, were not effective per se, but were changed to effective compounds by adding a lipophilic moiety. Using our study findings, we propose improvements for dietary habits with experimental evidence, and provide a basis for the development of novel small molecules as disease-modifying drugs for AD.

Shortened lifespan induced by a high-glucose diet is associated with intestinal immune dysfunction in Drosophila sechellia.

Organisms can generally be divided into two nutritional groups: generalists that consume various types of food and specialists that consume specific types of food. However, it remains unclear how specialists adapt to only limited nutritional conditions in nature. In this study, we addressed this question by focusing on Drosophila fruit flies. The generalist Drosophila melanogaster can consume a wide variety of foods that contain high glucose levels. In contrast, the specialist Drosophila sechellia consumes only the Indian mulberry, known as noni (Morinda citrifolia), which contains relatively little glucose. We showed that the lifespan of D. sechellia was significantly shortened under a high-glucose diet, but this effect was not observed for D. melanogaster. In D. sechellia, a high-glucose diet induced disorganization of the gut epithelia and visceral muscles, which was associated with abnormal digestion and constipation. RNA-sequencing analysis revealed that many immune-responsive genes were suppressed in the gut of D. sechellia fed a high-glucose diet compared with those fed a control diet. Consistent with this difference in the expression of immune-responsive genes, high glucose-induced phenotypes were restored by the addition of tetracycline or scopoletin, a major nutritional component of noni, each of which suppresses gut bacterial growth. We propose that, in D. sechellia, a high-glucose diet impairs gut immune function, which leads to a change in gut microbiota, disorganization of the gut epithelial structure and a shortened lifespan.

Relationship between communicative and critical health literacy, health information sources, and participation in health checkups among middle-aged Japanese community residents.

We assessed the relationship between health literacy and participation in health checkups among middle-aged Japanese community residents. Additionally, we explored the health information sources related to participation in health checkups among those with low, medium, and high health literacy. This mail survey using a self-administered questionnaire was conducted in 2020 and included 33,902 community residents with National Health Insurance (NHI), aged 40-64 years from five cities in Osaka Prefecture, Japan. Of these, 12,446 (36.7%) agreed to participate in the survey. After exclusion of those with regular visits to medical institutions and those with missing data, the analysis included 3582 participants. Health literacy was measured by the Communicative and Critical Health Literacy (CCHL) scale, and participants were classified into three groups (low, medium, and high health literacy groups) by the tertiles of CCHL scale score. After adjusting for confounding factors, the multivariable-adjusted odds ratios for non-participation in health checkups were 1.20 (95% CI 1.01-1.43, p = 0.039) in the medium health literacy group and 1.47 (95% CI 1.20-1.80, p < 0.001) in the low health literacy group compared with the high health literacy group. Additionally, some health information sources were associated with participation in health checkups in the medium and high health literacy groups, whereas none of the health information sources were associated with participation in health checkups in the low health literacy group. We believe that it is important to develop materials and interventions aimed at low health literacy populations to promote participation in health checkups.

Divergence of Drosophila species: Longevity and reproduction under different nutrient balances.

How nutrition impacts growth, reproduction and longevity is complex because relationships between these life events are difficult to disentangle. As a first step in sorting out these processes, we carried out a comparative analysis of related species of Drosophila with distinct feeding habits. In particular, we examined life spans and egg laying of two generalists and three specialists on diets with distinct protein-to-carbohydrate ratios. In contrast to the generalist D. melanogaster, adult males of two specialists, D. sechellia and D. elegans, lived longer on a protein-rich diet. These results and our previous studies collectively show that the diet to which larvae of each specialist species have adapted ensures a longer life span of adult males of that same species. We also found a species-specific sexual dimorphism of life span in the above two specialists regardless of the diets, which was in sharp contrast to D. melanogaster. In D. melanogaster, males lived longer than females, whereas females of D. sechellia and D. elegans were longer-lived than males, and those specialist females were exceedingly low in egg production, relative to the other species. We discuss our findings from perspectives of mechanisms, including a possible contribution of egg production to life span.

Effect of Dietary Nori (Dried Laver) on Blood Pressure in Young Japanese Children: An Intervention Study.

BACKGROUND: Few studies have examined the association between seaweed intake and blood pressure in children. We conducted an intervention study to investigate whether seaweed intake affects blood pressure. METHODS: Subjects were children aged 4 to 5 years attending a preschool in Aichi Prefecture, Japan, in 2010. Among 99 students, 89 (89.9%) were enrolled in our study. Nori (dried laver), an edible seaweed widely consumed in Japan, was used as a dietary intervention. Children in the intervention group were asked to consume 1.76 grams per day of roasted nori in addition to standard meals for 10 weeks. Children in the control group consumed their usual diet. Before the intervention and at the 10th week of the intervention, children's blood pressure was measured three times successively using an automated sphygmomanometer with subjects in a sitting position. Changes in systolic (SBP) and diastolic blood pressure (DBP) were compared between 55 children in the intervention group and 26 in the control group after adjustment for SBP and DBP before the intervention. RESULTS: Changes in SBP were -8.29 mm Hg in the intervention group and +0.50 mm Hg in the control group (P for difference in change = 0.051). Changes in DBP were -6.77 mm Hg in the intervention group and -0.05 mm Hg in the control group (P = 0.031). In girls, no difference in blood pressure changes was found between the intervention and control groups. CONCLUSION: Nori intake lowered DBP level in boys. Seaweed intake might have preventive effects on elevated blood pressure in childhood.

Association between exposure to household smoking and dental caries in preschool children: a cross-sectional study.

BACKGROUND: We aimed to examine the association of exposure to environmental tobacco smoke with dental caries among preschool children. Exposure to environmental tobacco smoke was assessed in terms of urinary cotinine concentrations and pack-years of exposure to smoking by parents and other family members at home. METHODS: This cross-sectional study included 405 preschool children aged 3-6 years from two preschools in Japan in 2006. Information on the smoking habits of family members living with the child was obtained from parent-administered questionnaires. Dental examination was conducted to assess dental caries, that is, decayed and/or filled teeth. Urinary cotinine levels were measured using first-void morning urine samples. RESULTS: Overall, 31.1% of the children had dental caries, and 29.5% had decayed teeth. Exposure to current maternal and paternal smoking was positively associated with the presence of dental caries after controlling for covariates. More than three pack-years of exposure to maternal smoking and more than five pack-years of exposure to smoking by all family members were significantly associated with the presence of dental caries as compared with no exposure (odds ratio [OR] = 5.55, 95% confidence interval [CI] = 2.17-14.22, P for trend < 0.001 and OR = 2.00, 95% CI = 1.12-3.58, P for trend = 0.004, respectively). These exposure variables were similarly associated with the presence of decayed teeth (OR = 2.92, 95% CI = 1.23-6.96, P for trend = 0.01 and OR = 1.75, 95% CI = 0.96-3.20, P for trend = 0.03, respectively). As compared with lowest tertile of the urinary cotinine level, the highest tertile of the urinary cotinine level was significantly associated with the presence of dental caries as well as decayed teeth; the ORs for the highest vs. lowest tertile of urinary cotinine levels were 3.10 (95% CI = 1.71-5.63, P for trend = 0.012) and 2.02 (95% CI = 1.10-3.70, P for trend = 0.10), respectively. CONCLUSIONS: These data suggest that exposure to tobacco smoke may have a dose-dependent influence on the development of caries.

Associations of Acrylamide Intake With Urinary Sex Hormone Levels Among Preschool-Age Japanese Children.

Acrylamide may affect the sex hormone system in the prepubertal period. This study examined the cross-sectional associations between dietary acrylamide intake and sex hormone levels among preschool-age Japanese children. The study was conducted in 2006 among 230 boys and 198 girls aged 3-6 years in Aichi, Japan. Acrylamide intake was assessed using 3-day diet records. Urinary concentrations of estrone, estradiol, testosterone, and androst-5-ene-3ß, 17ß diol (hereafter referred to as androstenediol) were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry. Sex hormone levels were adjusted for urinary creatinine levels. The estimated acrylamide intake was 1.00 µg/kg of body weight per day. After controlling for age and other covariates, acrylamide intake was significantly positively associated with urinary levels of testosterone and androstenediol in boys. On average, boys in the highest quartile of acrylamide intake had 96.9% higher testosterone (95% confidence interval: -1.8, 295; P for trend = 0.048) and 34.5% higher androstenediol levels (95% confidence interval: -5.9, 92.3; P for trend = 0.04) than boys in the lowest quartile. In girls, there were no significant associations between acrylamide intake and the hormones measured. Acrylamide intake may alter androgen metabolism in preschool-age boys. Because this is a first observation, our findings require confirmation in additional studies.

Nutrient-dependent increased dendritic arborization of somatosensory neurons.

Suboptimal nutrition imposes developmental constraints on infant animals, which marshal adaptive responses to eventually become mature adults. Such responses are mounted at multiple levels from systemic to cellular. At the cellular level, the underlying mechanisms of cell proliferation control have been intensively studied. However, less is known about how growth of postmitotic and morphologically complex cells, such as neurons, is controlled by nutritional status. We address this question using Class I and Class IV dendritic arborization neurons in Drosophila larvae. Class IV neurons have been shown to sense nociceptive thermal, mechanical and light stimuli, whereas Class I neurons are proprioceptors. We reared larvae on diets with different protein and carbohydrate content throughout larval stages and examined how morphologies of Class I or Class IV neurons were affected. Dendritic arbors of Class IV neurons became more complex when larvae were reared on a low-yeast diet, which contains lower amounts of amino acids and other ingredients, compared to a high-yeast diet. In contrast, such low-yeast-dependent hyperarborization was not seen in Class I neurons. The physiological and metabolic implications of the hyperarborization phenotype are discussed in relation to a recent hypothesis that Class IV neurons sense protein-deficient stress and to our characterization of how the dietary yeast contents impacted larval metabolism.

Technique of totally robotic delta-shaped anastomosis in distal gastrectomy.

BACKGROUND: We aimed to clarify the utility of delta-shaped anastomosis (Delta), an intracorporeal Billroth-I anastomosis-based reconstruction technique used after laparoscopy-assisted distal gastrectomy (LADG), in robot-assisted distal gastrectomy (RADG). METHODS: RADG was performed in patients with clinical Stage I gastric cancer, and reconstruction was performed using Delta. The Delta procedure was the same as that performed after LADG, and the operator practiced the procedure in simulated settings with surgical assistants before the operation. After gastrectomy, the scope and robotic first arm were reinserted from separate ports on the right side of the patient. Then, a port on the left side of the abdomen was used as the assistant port from which a stapler was inserted, with the robotic arm in a coaxial mode. The surgical assistant performed functional end-to-end anastomosis of the remnant stomach and duodenal stump using a powered stapler. RESULTS: The mean anastomotic time in four patients who underwent Delta after RADG was 16.5 min. All patients were discharged on the post-operative day 7 without any post-operative complications or need for readmission. CONCLUSIONS: Pre-operative simulation, changes in ports for insertion of the scope and robotic first arm, continuation of the coaxial operation, and use of a powered stapler made Delta applicable for RADG. Delta can be considered as a useful reconstruction method.

Technique of Roux-en-Y reconstruction using overlap method after laparoscopic total gastrectomy for gastric cancer: 100 consecutively successful cases.

BACKGROUND: We have established a standard procedure for Roux-en-Y (RY) reconstruction in laparoscopic total gastrectomy (LTG) using esophagojejunostomy by the overlap method (OL). We report on our RY reconstruction technique and special approaches, and evaluate the usefulness of our reconstruction method based on the surgical results of 100 patients we have experienced to date. METHODS: We performed LTG in 100 patients with gastric cancer. After total gastrectomy using five ports, the resected stomach was extracted through a small laparotomy. Through that, we performed sacrifice of the jejunum, Y limb anastomosis, creation of the lifted jejunum. As the OL, a side-to-side anastomosis of the lifted jejunum to the esophageal stump was laparoscopically performed using a linear stapler in an isoperistaltic direction, and the entry hole was closed with full-thickness suturing. The lifted jejunum was fixed with suture to the duodenal stump at a location where the esophagojejunostomy site was made linear, and the duodenal stump was buried. The mesenteric gap was laparoscopically closed with suture. RESULTS: The median operative time in 100 patients undergoing LTG was 385 min, the median blood loss was 65 mL, and the median time required for the OL was 32 min. The mean hospitalization period was 10 days, and postoperative complications included bleeding requiring reoperation in one patient; other complications such as pancreatic fistula in five patients (5 %) were treated conservatively. No complication associated with anastomosis occurred. CONCLUSION: In RY reconstruction using the OL, there were no complications associated with the anastomosis site in 100 consecutive patients, such as anastomotic leak or stenosis, indicating that it is a very useful and safe reconstruction method.

Intestinal metaplasia in Barrett's oesophagus may be an epiphenomenon rather than a preneoplastic condition, and CDX2-positive cardiac-type epithelium is associated with minute Barrett's tumour.

AIMS: Although intestinal-type epithelium in Barrett's oesophagus has been traditionally recognized as having a distinct malignant potential, whether this also holds true for cardiac-type epithelium remains controversial. The aim of this study was to identify a type of epithelium that is highly associated with Barrett's tumour. METHODS AND RESULTS: We analysed tumours and the corresponding background mucosa with special regard to tumour size in 40 cases of superficial Barrett's tumour by using immunohistochemical staining for CDX2, CD10, MUC2, MUC5AC, and MUC6. Intestinal metaplasia in tumour-adjacent mucosa was not associated with tumour size, but was significantly correlated with the extent of Barrett's oesophagus (P < 0.001). The majority (69.2%, 9/13) of small tumours (≤10 mm) had no intestinal metaplasia in adjacent non-neoplastic mucosae. Minute (≤5 mm) tumours were significantly associated with a gastric immunophenotype (P < 0.001). Purely gastric-immunophenotype tumour cells expressed CDX2, and cardiac-type epithelium adjacent to small tumours also showed low-level CDX2 expression. CONCLUSIONS: Our data suggest that intestinal metaplasia in Barrett's oesophagus is an epiphenomenon rather than a preneoplastic condition, and that CDX2-positive cardiac-type epithelium is highly associated with minute Barrett's tumour. Further prospective studies are needed to evaluate the risk of malignancy of cardiac-type epithelium with regard to sub-morphological intestinalization.

Pulmonary infections following immunosuppressive treatments during hospitalization worsen the short-term vital prognosis for patients with connective tissue disease-associated interstitial pneumonia.

OBJECTIVE: Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP. METHODS: A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model. RESULTS: A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age ≥ 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates. CONCLUSION: Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD-IP is indispensable for improving the short-term vital prognosis of these patients.

S-nitrosated α-1-acid glycoprotein kills drug-resistant bacteria and aids survival in sepsis.

Treating infections with exogenous NO, which shows broad-spectrum antimicrobial activity, appears to be effective. Similar to NO biosynthesis, biosynthesis of α-1-acid glycoprotein variant A (AGPa), with a reduced cysteine (Cys149), increases markedly during inflammation and infection. We hypothesized that AGPa is an S-nitrosation target in acute-phase proteins. This study aimed to determine whether S-nitrosated AGPa (SNO-AGPa) may be the first compound of this novel antibacterial class against multidrug-resistant bacteria. AGPa was incubated with RAW264.7 cells activated by lipopolysaccharide and interferon-γ. The antimicrobial effects of SNO-AGPa were determined by measuring the turbidity of the bacterial suspensions in vitro and survival in a murine sepsis model in vivo, respectively. Results indicated that endogenous NO generated by activated RAW264.7 cells caused S-nitrosation of AGPa at Cys149. SNO-AGPa strongly inhibited growth of gram-positive, gram-negative, and multidrug-resistant bacteria and was an extremely potent bacteriostatic compound (IC(50): 10(-9) to 10(-6) M). The antibacterial mechanism of SNO-AGPa involves S-transnitrosation from SNO-AGPa to bacterial cells. Treatment with SNO-AGPa, but not with AGPa, markedly reduced bacterial counts in blood and liver in a mouse sepsis model. The sialyl residues of AGPa seem to suppress the antibacterial activity, since SNO-asialo AGPa was more potent than SNO-AGPa.

The risk of serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors decreased over time: a report from the registry of Japanese rheumatoid arthritis patients on biologics for long-term safety (REAL) database.

To investigate changes in the risk for serious infections (SIs) over time in Japanese rheumatoid arthritis (RA) patients treated with tumor necrosis factor inhibitors (TNFIs). This prospective cohort study included Japanese RA patients who began treatment with a TNFI from 2005 to 2007 (2005 group, n = 716, 634.2 patient years [PY]) and from 2008 to 2011 (2008 group, n = 352, 270.1 PY) at the time or after their enrollment in the registry of Japanese RA patients on biologics for long-term safety (REAL) database. Patients were observed for 12 months or until discontinuation of their initial TNFI in the REAL database. Drug discontinuation reasons and retention rates were analyzed. Incidence rates of serious adverse events (SAEs) were calculated with 95 % confidence intervals (CIs). The Cox proportional hazard model was applied to estimate the risk for SIs. The retention rate in the 2008 group was significantly lower than the 2005 group (p < 0.001). Discontinuation rates due to lack of efficacy or good control for the 2008 group were significantly higher than the 2005 group (p < 0.001). The crude incidence rate ratios comparing the 2008 group with the 2005 group for SAEs were 0.93 (95 % CI 0.65-1.34) and for SIs were 0.50 (0.24-1.03). The 2008 group had significantly lower risk for SIs than the 2005 group after adjusting for covariates (hazard ratio: 0.43 [0.20-0.93]). These results indicate significant decrease of the risk for SIs with TNFI treatment over time; this may be explained by evidence-based risk management of RA patients given TNFIs.

Successful treatment of eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) with rituximab in a case refractory to glucocorticoids, cyclophosphamide, and IVIG.

A 44-year old woman with eosinophilic granulomatosis with polyangiitis (EGPA) developed sequential paralysis of different cranial nerves despite treatments including methylpredonisolone pulse therapy, intravenous immunoglobulins (IVIG), and cyclophosphamide. Infusions of rituximab ameliorated her neurological symptoms and serological inflammatory findings. Rituximab, a specific B cell-targeting therapy, might offer an alternative for refractory EGPA with possible advantages of cost and ease of use compared to IVIG, which also targets (at least in part) B lymphocytes and immunoglobulin production.