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Highlight Endoscopic ultrasound-guided hepaticogastrostomy with a partially covered metal stent has a potential risk of stent occlusion due to hyperplasia at an uncovered portion of the stent. Matsubara and colleagues report that radiofrequency ablation of hyperplasia with additional placement of an uncovered metal stent is useful for preventing recurrent stent occlusion.

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting.Me...

In the management of patients with pancreatic cancer and cholangiocarcinoma, various issues other than antitumor therapy will develop: obstructive jaundice due to the tumor invasion to the bile duct or the biliojejunal anastomotic stricture after pancreatoduodenectomy; recurrent pancreatitis or pancreatic pain due to the pancreatojejunal anastomotic stricture after pancreatoduodenectomy; cholecystitis due to the placement of biliary self-expandable metal stents; postoperative pancreatic fistulas with or without peripancreatic fluid collections, and severe abdominal pains due to the tumor invasion to the celiac plexus. Traditionally, endoscopic transpapillary or percutaneous approaches were applied for the treatment of such problems; however, they have many limitations in the success and the quality of life of patients. To date, endoscopic ultrasound (EUS)-guided interventions have emerged to resolve these issues as minimally invasive therapies. In this chapter, EUS-guided interventional procedures in the management of pancreatic cancer and cholangiocarcinoma will be described.

Background: The selection of an approach route in endoscopic ultrasound-guided rendezvous (EUS-RV) for failed biliary cannulation is complicated. We proposed an algorithm for EUS-RV. Methods: We retrospectively evaluated consecutive EUS-RV cases between April 2017 and July 2020. Puncturing the distal extrahepatic bile duct (EHBD) from the duodenal second part (D2) (DEHBD/D2 route) was attempted first. If necessary, puncturing the proximal EHBD from the duodenal bulb (D1) (PEHBD/D1 route), puncturing the left intrahepatic bile duct (IHBD) from the stomach (LIHBD/S route), or puncturing the right IHBD from the D1 (RIHBD/D1 route) were attempted in this order. Results: A total of 16 patients were included. The DEHBD/D2 route was used in 10 (62.5%) patients. The PEHBD/D1 route was attempted in five (31.3%) patients, and the biliary puncture failed in one patient in whom the RIHBD/D1 route was used because of tumor invasion to the left hepatic lobe. The LIHBD/S route was applied in one (6.3%) patient. Successful biliary cannulation was achieved in all patients eventually. The time from the puncture to the guidewire placement in the DEHBD/D2 route (3.5 min) was shorter than that in other methods (14.0 min) (p = 0.014). Adverse events occurred in one (6.3%) patient with moderate pancreatitis. Conclusions: The proposed algorithm might be useful for the selection of an appropriate approach route in EUS-RV.

Background: Posttraumatic stress disorder (PTSD) has been associated with increased inflammation. C-reactive protein (CRP) is a marker of systemic inflammation, and recently, single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with increased blood CRP protein levels and illness severity in PTSD patients. However, the mechanism by which the CRP SNPs are involved in PTSD remains unclear. Here we investigated the association of CRP genetic variation with blood proinflammatory protein levels, symptomatology, and cognitive function, and further explored the moderating effect of childhood maltreatment history, in adult patients with PTSD. Methods: Fifty-seven Japanese civilian women with PTSD and 73 healthy control women were enrolled. Three SNPs in the CRP gene, namely rs2794520, rs1130864, and rs3093059, were genotyped, and analyses focused on rs2794520 (T/C). Serum levels of high-sensitivity CRP (hsCRP), high-sensitivity tumor necrosis factor-α (hsTNF-α), and interleukin-6 were measured. PTSD symptoms were evaluated by the Posttraumatic Diagnostic Scale. Cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status. Childhood maltreatment history was assessed by the Childhood Trauma Questionnaire. Results: Patients with the rs2794520 CC/CT genotype, compared to those with the TT genotype, showed significantly higher levels of hsCRP (p=0.009) and hsTNF-α (p=0.001), more severe PTSD symptoms (p=0.036), and poorer cognitive function (p=0.018). A two-way analysis of variance revealed a significant genotype-by-maltreatment interaction for more severe PTSD avoidance symptom (p=0.012). Limitations: The relatively small sample size limited our findings. Conclusions: These findings may provide an insight into the etiology of PTSD from the inflammatory perspective.

Abatacept may exert its clinical effect on rheumatoid arthritis (RA) by suppressing anti-cyclic citrullinated peptide (CCP) antibody production. This study was undertaken to test this hypothesis by examining the changes of disease activity of RA and anti-CCP antibody levels over time after starting abatacept. Sixty Japanese RA patients who started abatacept were included in this multicenter, prospective observational study. Simple Disease Activity Index (SDAI) and anti-CCP antibody levels were evaluated at 12, 24, and 52 weeks. The mean SDAI score significantly decreased within 12 weeks after starting abatacept and was maintained thereafter. On the contrary, the mean anti-CCP antibody levels did not change until 52 weeks. At the individual level, there were substantial changes of anti-CCP antibody levels, but these were not correlated with the changes of disease activity at any time points. Thus, abatacept reduces the disease activity of RA independently of modulating anti-CCP antibody production.

IntroductionTranscranial direct current stimulation (tDCS) is a potentially novel strategy for cognitive enhancement in patients with disorders. We present a study protocol for a randomised controlled trial designed to evaluate the safety and efficacy of tDCS combined with cognitive tasks on cognition in such patients.Method and analysisThis is a two-arm, parallel-design, randomised, sham-controlled trial, in which participants and raters will be blinded at a single centre. Stratified randomisation will be conducted, and a randomisation sequence will be generated through the Electronic Data Capture system. Patients who met the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for neurocognitive disorders will be recruited and randomised to receive either active (2 mA for 20 min) or sham (stimulation ramped up and down for 1 min) stimulation in 10 sessions over five consecutive days. A direct current will be transferred by a 35 cm2 saline-soaked sponge electrode. An anode will be placed over the left dorsolateral prefrontal cortex, and a cathode will be placed over the right supraorbital cortex. Calculation tasks will be conducted in both arms as a cognitive task for 20 min during the stimulation. This task consists of basic arithmetic questions, such as single-digit addition, subtraction, multiplication and division. The primary outcome will be the mean change in the Alzheimer Disease Assessment Scale–cognition at Day 5 after baseline. Depressive symptoms, as measured by the geriatric depression scale, and quality of life, as measured by the Medical Outcomes Study 36-item Short-Form Health Survey, will also be assessed. Data will be collected at baseline, within 3 days following the final stimulation and 1 month thereafter. The estimated sample size is 46 per group based on the assumptions that an estimated mean difference is −1.61 and SD is 2.7. Mixed models for repeated measures will be used for the statistical analysis.Ethics and disseminationThe National Center of Neurology and the Psychiatry Clinical Research Review Board (CRB3180006) approved this study. The results of this study will be published in a scientific peer-reviewed journal.Trial registration detailsJapan Registry of Clinical Trials jRCTs032180016.

This paper reports an investigation of the effects of silica particles contained in mold resin to the light extraction efficiency of light-emitting diode (LED) packaging (PKG) using ray-tracing simulations. The light extraction efficiencies, namely, luminous and radiant flux of the rays emitted from the PKG, are improved with the silica particles. The silica particles cause the scattering of the rays in the mold resin of the LED PKG. If the scattering can be generated properly, the light extraction efficiency can be improved. Varying the volume percentage of the silica particles, its effects to the light extraction efficiency are confirmed. Finally, we could confirm the improvement of luminous higher than 0.5 lm and radiant flux higher than 0.02 W respectively from the simulation results.

This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice.We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria.Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR2.6 at the final follow-up. The retention rate at 36 months was 68.2 %.In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

Cortical fast-spiking (FS) interneurons are electrically interconnected through gap junctions and form dendritic net structures extending over different functional columns. Here we investigated how pyramidal cells regulate FS cell network activity. Using paired recordings and glutamate puff stimulations, we found that FS cell pairs connected by electrical synapses shared common inputs from surrounding pyramidal cells more frequently than those unconnected or connected only by chemical synapses. Experimental and simulation results suggest that activity spread evoked by common inputs to electrically connected FS cells depends on network state. When cells were in the depolarized state, common inputs to electrically connected cells enhanced spike induction and induced inhibitory effects in surrounding FS cells. By contrast, in the hyperpolarized state, either sub- or suprathreshold inputs produced depolarizing potentials in nearby cells. Our results suggest that globally connected FS cell networks are locally regulated by pyramidal cells in an electrical connection- and network state-dependent manner.

Higher-order motor cortices, such as the secondary motor area (M2) in rodents, select future action patterns and transmit them to the primary motor cortex (M1). To better understand motor processing, we characterized "top-down" and "bottom-up" connectivities between M1 and M2 in the rat cortex. Somata of pyramidal cells (PCs) in M2 projecting to M1 were distributed in lower layer 2/3 (L2/3) and upper layer 5 (L5), whereas PCs projecting from M1 to M2 had somata distributed throughout L2/3 and L5. M2 afferents terminated preferentially in upper layer 1 of M1, which also receives indirect basal ganglia output through afferents from the ventral anterior and ventromedial thalamic nuclei. On the other hand, M1 afferents terminated preferentially in L2/3 of M2, a zone receiving indirect cerebellar output through thalamic afferents from the ventrolateral nucleus. While L5 corticopontine (CPn) cells with collaterals to the spinal cord did not participate in corticocortical projections, CPn cells with collaterals to the thalamus contributed preferentially to connections from M2 to M1. L5 callosal projection (commissural) cells participated in connectivity between M1 and M2 bidirectionally. We conclude that the connectivity between M1 and M2 is directionally specialized, involving specific PC subtypes that selectively target lamina receiving distinct thalamocortical inputs.

Our previous study reported a frequent detection of human papillomavirus (HPV) genome in primary lung adenocarcinomas of the recurrent patients who were responsive to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, suggesting that HPV presence in lung cancer may be related to a genetic background related to EGFR mutations. The present study examined the association between the HPV presence and mutations in exons 19 and 21 of EGFR gene in Japanese lung cancer patients. Thirteen (31%) out of 42 cases had EGFR mutations. Although these mutations were tended to be observed in females, non-smokers, or adenocarcinomas, there was no statistically significant associations. HPV DNA was found in 7/42 (17%) lung tumors. The frequency of HPV presence did not differ in histological types. The presence of HPV DNA was significantly related to EGFR mutations (P=0.021), especially in adenocarcinomas of the lung (P=0.014). HPV-positive lung tumors accounted for 38% and 7% of those with and without EGFR mutations, respectively. Our results suggest that EGFR mutations are associated with HPV presence in Japanese patients with lung cancer.

We describe a case of hypertrophic cranial pachymeningitis (HCP) associated with Wegener’s granulomatosis (WG) in a 60-year-old man presenting with chronic headache and multiple cranial nerve neuropathies. A test for antibodies to the neutrophil cytoplasmic protein myeloperoxidase (MPO-ANCA) was positive in this case. We review the literature on perinuclear (p)-ANCA-related HCP, including our case. This case indicates the link between MPO-ANCA-positive WG and HCP.

We describe a rare case of systemic vasculitis associated with α1-antitrypsin (α1-AT) deficiency. Mutational analysis of the α1-AT gene in this patient revealed a homozygous α1-AT Mnichinan variant. α1-AT possesses broad-spectrum inhibitory activity against many serine proteases, including human neutrophil elastase, to help maintaining the crucial balance between proteases and protease inhibitors. The increase in free protease activity in the context of α1-AT deficiency may induce exacerbation of the vasculitis. This serious genetic defect severely affects the balance between a protease and a protease inhibitor at the pathological site.(Internal Medicine 42: 619-623, 2003)

Eighty-four female outpatients with systemic lupus erythematosus (SLE) who are able to live on their own were investigated. We statistically analyzed the relationship between emotional instability based on psychological tests (Cornell Medical Index), and physical, medical, and social factors based on both our clinical records and original questionnaires. The emotional instability was related to not "working," an older "age at the time of SLE diagnosis," being "anxious about the adverse effects of steroids," or not "understanding the details of the disease and treatment at the time SLE treatment was started." No relationship with previously experienced physical factors was observed. In addition, no relationship with disease activity was observed either. We identified the characteristic correlation between emotional instability and medical and social factors in this study. Paying close attention to these factors may thus be useful in both preventing the appearance of psychological problems and developing effective early treatment strategies.

The subjects consisted of 84 female SLE outpatients who were all over 20 years of age. These patients were able to maintain relatively stable physical conditions and lead normal daily lives, and they were regularly treated at the outpatient clinic. All subjects were Japanese. Psychological features (trait anxiety, state anxiety, depression and suicide ideation) were evaluated using psychological tests, and the relationships between the respective psychological features and background factors were statistically evaluated using stepwise multiple logistic regression analyses. In this study, we found that 'the self-evaluation of not having understood SLE at the time of starting SLE treatment' was the background factor significantly affecting depression or trait anxiety. 'No spouse' had a statistically significant effect on depression, and 'self-awareness as problems of side-effects due to steroids' had a statistically significant effect on state anxiety. We also found 'human relations among family members' and 'high daily steroid dosage' to be significantly correlated with suicide ideation. However, there were no correlations between the psychological features and 'disease activity at the time of investigation' or 'history of neuropsychiatric diseases'. In female SLE outpatients, performing psychological approaches focusing on 'understanding SLE at the beginning of treatment', 'the human relationships among family members', or 'issues related to steroid therapy' may be useful for the early treatment or prevention of various major mental problems.

Interferon (IFN)-α therapy may induce, reveal, or exacerbate various autoimmunerelated disorders. We describe a 48-year-old female patient who developed muscle waakness during IFN-α therapy given for hepatitis C virus-associated chronic active hepatitis. This symptom diminished slightly after discontinuation of the therapy, but she then began to complain of Raynaud’s phenomenon, swelling of bilateral dorsal hands and dysphagia. Accompanied by an elevation of serum antinuclear antibody, the subsequent development of polymyositis (PM) and progressive systemic sclerosis was considered to have been induced by the IFN-α.

Genetic factors seem to play a significant role in susceptibility to systemic lupus erythematosus (SLE). We previously described the amino acid polymorphism (Val14Met) within the IFN-gamma receptor 1 (IFN-gammaRI), and that the frequency of the Metl4 allele in SLE patients was significantly higher than that of the healthy control population [Tanaka et al. (1999) Immunogenetics 49, 266-271]. We also found an amino acid polymorphism (Gln64Arg) within IFN-gamma receptor 2 (IFN-gammaR2). Since the IFN-gamma receptor is a complex consisting of IFN-gammaR1 and IFN-gammaR2, we searched for the particular combination of two kinds of amino acid polymorphisms found within the IFN-gamma receptor which plays a prominent role in susceptibility to SLE. The greatest risk of the development of SLE was detected in the individuals who had the combination of IFNGR1 Met14/Val14 genotype and IFNGR2 Gln64/Gln64 genotype.

Three adult patients with chronic active Epstein-Barr virus infection (CAEBV) had high anti-EBV-VCA antibody, positive anti-EA, low anti-EBNA and were associated with systemic lymphadenopathies and immunosuppression. The case 1 and 2 had elevated serum immunoglobulin levels, and recurrent infections, and case 3 showed pancytopenia. These 3 cases developed both EBV and latent membrane protein (LMP) positive malignant histiocytosis, EBV positive but LMP negative plasmacytoma, and EBV negative acute myelogeneous leukemia, respectively. It was suggested that CAEBV belonged to high risk groups for the development of malignant neoplasms. Since HLA of the case 1 and his father was identical, we conducted a in vitro cytotoxicity test using EBV transformed autologous B lymphocytes, K562 cells, and Raji cells to clarify the association of immunosuppression and HLA. The case 1 showed a low level of specific cytotoxicity to autologous EBV transformed B cells, while his parents were negative for the specific cytotoxicity. The patient and his parents developed inducible cytotoxicity to all targets after in vitro incubation of peripheral mononuclear cells with recombinant interleukin 2 (rIL-2) for 7 days. The patient and his mother showed lower enhancement of cytotoxicity, while HLA identical father could induce good cytotoxic activity to all targets as well as normal controls, indicating that a low IL-2 induced cytotoxic activity observed in CAEBV was independent of HLA associated immunoregulation at least in the case 1. Further studies are required to clarify the exact mechanisms responsible for the development of CAEBV.

In the present study we investigated the effect of a potent anti-inflammatory cytokine, interleukin (IL)-10, on the development of collagen-induced arthritis (CIA) in mice. Each DBA1/J mouse was immunized with 200 micrograms of native collagen and followed by booster injections at 3 weeks. rmIL-10 was injected i.p. daily at a dose of 100 ng/mouse. Mice were divided into four groups according to the administration period of rmIL-10. As a result, a 48-day course of IL-10 treatment significantly suppressed the severity of arthritis. Among the 4 groups, the most pronounced suppression was observed in the group in which IL-10 was given from day 0 to 21. On the other hand, there were no significant differences in the serum IgG anti-type II collagen (CII) titers between the four groups. Moreover, the production of cytokines (IL-6 and tumor necrosis factor-alpha (TNF-alpha)) and other mediators (prostaglandin E2 (PGE2) and nitric oxide (NO)) by peritoneal macrophages seemed to show no clear correlation with the severity of arthritis in mice. These results raise the possibility that IL-10 might be a useful agent for suppressing the progression and the development of CIA in mice.

症例は, 36歳,女性.平成3年3月, 39°Cの発熱を主訴に近医に入院.全身性エリテマトーデス(SLE)と診断され同年4月よりprednisolone 60mg/dayの治療が開始されたがステロイド減量困難のため,平成3年10月7日当科に入院した.入院時hemophagocytic syndromeによる播種性血管内凝固症候群(DIC)の状態であったが呼吸器症状はなく,胸部X線像も正常であった. 10月9日より38°C以上の発熱が続き10月11日より咳嗽も出現するようになり,左肺上葉中心の大葉性肺炎が急速に進行したが, erythromycinが著効した.血清抗体価測定よりLegionella bozemanii肺炎と診断した.また尿中よりcytomegalovirus (CMV)を検出しganciclovirを使用したところ, hemophagocytosisおよびDICは改善した.本症例はCMV感染によるinfection-associated hemophagocytic syndromeを発症したSLEに,レジオネラ症でもまれなL. bozemanii肺炎を合併した1例で,免疫能低下の関与が示唆された.

A 51-year-old man with non-Hodgkin's lymphoma (NHL) was treated with high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). Although he had HLA-DRB1 0405 and a positive rheumatoid factor, he was unlikely to develop rheumatoid arthritis (RA) according to diagnostic criteria. However, the patient developed RA 40 days after transplantation. Our experience suggests that the systemic autoimmune disease, RA, may occur in patients with predisposing factors after autologous PBSCT.

Behçet's disease is a multisystem inflammatory disorder with unknown etiology. It has been shown that the titer of plasma complement component 9 (C9) is a good indicator of the disease activity. Therefore, the involvement of C9 in the pathogenesis of Behçet's disease has been suggested. We report a case of Behçet's disease associated with complete C9 deficiency (C9D) carrying the homozygous nonsense mutation at Arg-95 of C9 (R95X). The patient presented the typical characteristics of Behçet's disease, such as uveitis, recurrent oral aphthae and genital ulcers, and arthritis, suggesting that C9 does not play an essential role in the pathogenesis of Behçet's disease.

OBJECTIVE To elucidate the factors associated with poor prognosis of LEF-induced lung injury in patients with RA. METHODS The background and clinical and laboratory features of LEF-induced lung injury were examined and compared between patients who died of and who recovered from it. RESULTS Among 22 patients who developed LEF-induced lung injury, 9 died of and 13 recovered from it. The patients who died tended to have pre-existing interstitial pneumonia (8/9 vs 6/13, P = 0.07). The loading and maintenance doses, serum concentration of the LEF metabolite A771726 and administration period did not differ between the groups. Patients who died had more frequently hypoxaemia of

Objectives. The possible link between LEF and interstitial lung disease (ILD) has evoked increasing concern. The aim of the present study was to elucidate the prevalence and risk factors for newly developed and/or exacerbated ILD, based on post-marketing surveillance data, in which all RA patients receiving LEF were pre-registered and monitored for 24 weeks in Japan. Methods. We analysed data from a cohort of 5054 RA patients who were prescribed LEF since its launch in September 2003 in Japan. Multivariable logistic analysis was performed to identify the risk factors for newly developed and/or exacerbation of ILD. Results. Sixty-one (1.2%) of 5054 RA patients who received LEF were reported to have development and/or exacerbation of ILD as an adverse drug reaction to LEF, judged by the attending physicians. Multivariable logistic regression analysis identified pre-existing ILD [odds ratio (OR) 8.17; 95% CI 4.63, 14.4], cigarette smoking (3.12; 95% CI 1.73, 5.60), a low body weight ( 50 kg) (2.91; 95% CI 1.15, 7.37) and the use of a loading dose (3.97; 95% CI 1.22, 12.9) as independent risk factors for LEF-induced ILD. Conclusions. Pre-existing ILD was the most important risk factor for LEF-induced ILD. We suggest that LEF should not be prescribed for RA patients complicated with ILD.

全身性エリテマトーデス(SLE)の病態形成における補体系の関与をより明らかにするため,当科に入院した活動性SLE 60例を対象とし, SLEの臨床症状,検査所見とCH50, C3, C4との関係,臨床経過に伴うCH 50の変化,治療開始6ヵ月後にCH50の正常化した群,しなかった群の差異につき検討した. SLEの臨床症状,検査所見,治療において口腔潰瘍,腎症,溶血性貧血,抗DNA抗体高値,免疫複合体陽性,パルス療法施行群などにて補体が低下していた.臨床経過に伴うCH50の推移では治療前に腎症群で著明低値,一方, CNSループス群で軽度低値を示したが3ヵ月後, 6ヵ月後にはCH50は正常化しほぼ同程度の値となった.治療開始6ヵ月後にCH50が正常化しなかった例は24.3%であり,正常化しなかった群では正常化した群に比し,溶血性貧血の頻度が高く治療前のC4が低値であり,免疫抑制剤の使用頻度が低かった.

A 60-year-old rheumatoid arthritis (RA) female with lung fibrosis was treated with leflunomide (LEF) for only 12 days, and responded well. Twenty-five days after the withdrawal of the drug, she had fever, dyspnea, and an elevated serum C-reactive protein level. Chest CT revealed ground-glass opacities (GGOs) and consolidations forming a mosaic pattern, in lung fields including the upper, anterior and central areas, and honeycomb patterns in the lung bases and backs. The level of plasma A771726, an active metabolite of LEF, was still as high as that usually noted under LEF therapy. After pulsed steroid and cholestyramine administration, A771726 was depleted and she recovered. The peripheral blood lymphocyte count that had been approximately 1,000/microL, decreased to 220/microL just at the onset of lung injury, and rapidly and steadily returned to the preinjury level preceding recovery from the injury. Serum albumin level decreased in association with lung injury, and gradually returned to the preinjury level. Special caution is necessary when prescribing leflunomide to elderly patients with preexisting interstitial lung disease, and remains necessary until at least 1 month after its withdrawal.

Objectives: To carry out a phase I-II trial to elucidate the feasibility and efficacy of high dose cyclophosphamide (CY) supported by autologous peripheral blood stem cell transplantation (PBSCT) in the treatment of severe and refractory autoimmune disease (AD). Methods: Peripheral blood stem cells (PBSCs) were mobilised during haematological recovery after relatively high dose CY (2 g/m 2 ) for 2 days, followed by administration of granulocyte colony stimulating factor. After collecting PBSCs—more than 2×10 6 CD34+ cells/kg—by apheresis, CD34+ cells were immunologically selected and cryopreserved. Eight patients were enrolled—five had systemic sclerosis (SSc) alone, one had SSc with systemic lupus erythematosus, one amyopathic dermatomyositis (ADM), and one Wegener’s granulomatosis (WG). All of the patients were treated with high dose CY (50 mg/kg) for 4 days and autologous PBSCT. Results: Haematopoietic reconstitution was rapid and sustained. Toxicity due to the regimen included various infections such as pneumonia, sepsis, cystitis, herpes zoster, and acute heart failure. However, there was no treatment related mortality. Encouraging results were obtained after autologous PBSCT. Sclerosis of the skin was markedly improved in all of the patients with SSc. Interstitial pneumonia (IP), evaluated by Pao 2 , serum KL-6 levels, and pulmonary high resolution computed tomography, improved significantly. In a patient with ADM, severe and progressive IP also improved markedly. In a patient with WG, the size of the left orbital granuloma decreased substantially, resulting in reduction of the exophthalmos. Conclusions: These observations suggest that high dose CY with autologous PBSCT is feasible and may be effective in the treatment of severe and refractory AD.

Systemic lupus erythematosus (SLE) is characterized by multisystem inflammation and production of autoantibodies, which can generate immune complexes and may cause tissue damage through the recognition of an autoantigen. Although many factors have been proposed, such as genetic factors, environmental factors, hormonal action, viruses, and dysregulation of cytokine production, the cause of this disease is not well understood. It has been reported that the levels of interferon (IFN)-alpha in the sera of some SLE patients are elevated and that IFN-alpha induces maturation of monocytes into highly active antigen-presenting dendritic cells (DCs). We analyzed the association between IFN-alpha genotype and the risk of SLE to clarify whether IFN-alpha plays a central role in susceptibility to SLE. The results showed that no IFN-alpha genotype was significantly associated with the risk of SLE.

Cytokines have an important role in the pathogenesis and disease progression of immunoglobulin A (IgA) nephropathy. The aim of this study is to investigate the impact of gene polymorphisms of T helper cell subtype 1 (T(H)1)/T(H)2 cytokines, interferon-gamma (IFN-gamma), and interleukin-4 (IL-4) on IgA nephropathy in Japanese patients.We investigated IFN-gamma gene (IFNG) and IL-4 gene (IL4) polymorphisms in 96 patients with biopsy-confirmed IgA nephropathy who were followed-up for more than 3 years in our outpatient clinic and 61 healthy controls by polymerase chain reaction and direct sequencing methods. IFNG polymorphism was characterized as a microsatellite of intron 1. Four alleles were identified and designated IFNG 112, 114, 116, and 118, corresponding to 12, 13, 14, and 15 repeats, respectively. A variable number of tandem repeat (VNTR) polymorphisms of IL4 also were studied, and alleles were designated IL4 B1 and B2, corresponding to 2 and 3 repeats, respectively.In patients with IgA nephropathy, IFNG 114 allele and IFNG 114(+/+) genotype frequencies were significantly greater than in the healthy control group (60% versus 45%; P0.01 and 43% versus 23%; P0.05, respectively), but there was no difference between the IgA nephropathy and healthy control groups in frequencies of both IL4 VNTR allele and genotype. However, frequencies of IL4 B1 allele and B1/B1 genotype in patients with progressive IgA nephropathy (end-stage renal disease or doubling of serum creatinine level; n = 34) were significantly greater than corresponding values in the nonprogression group (n = 62; 79% versus 61%; P0.01 and 59% versus 34%; P0.05, respectively). We could not confirm an association between IgA nephropathy and polymorphisms of genes involved in the renin-angiotensin system.Our results suggest that IFN-gamma and IL-4 gene polymorphisms could influence disease susceptibility and disease progression in IgA nephropathy in Japanese patients. Am J Kidney Dis 41:371-379.

Objective Lupus nephritis, which shows various histologic patterns, is a serious complication of systemic lupus erythematosus (SLE). We previously demonstrated the importance of Th1 cell–mediated immune response in patients with diffuse proliferative lupus nephritis (DPLN). The aim of this study was to examine the relationship between the peripheral blood Th1/Th2 balance and the intrarenal immune response. Methods The Th1:Th2 ratio in peripheral blood was measured by intracellular staining for cytokines with flow cytometry. Immunohistochemical analysis of renal biopsy specimens was performed to clarify the characterization of local infiltrating cells in 3 groups of subjects: SLE patients with World Health Organization (WHO) class IV nephritis (DPLN) (group I; n = 13), SLE patients with WHO class V nephritis (group II; n = 9), and patients with minor glomerular lesions (group III; n = 7). In addition, the histologic activity index and chronicity index were evaluated and correlated with the Th1:Th2 ratio. Results Immunohistochemical studies showed higher numbers of CD68+ macrophages, CD3+ T cells, and interferon-γ–positive cells in group I than in groups II or III. Renal tissues from patients in group I also showed up-regulation of expression of osteopontin and CD40, with a small number of infiltrating T cells expressing interleukin-4. Overall, the Th1:Th2 ratio in group I patients (SLE with DPLN) was high and correlated significantly with the histologic activity index, but not with the chronicity index. Conclusion We have identified a predominance of Th1-type response in both peripheral and renal tissues of patients with DPLN, suggesting that the peripheral blood Th1:Th2 ratio directly reflects the local histopathologic findings. In patients with lupus nephritis, the peripheral blood Th1:Th2 ratio could be useful as a parameter that reflects the renal histologic activity or the strength of the local Th1 response.

A 72-year-old woman with 5-year history of essential hypertension developed peritoneal tuberculosis. The patient's hypertension, which had been well-controlled by long-acting nifedipine, deteriorated after the administration of rifampicin, an antitubercular agent. During use of nifedipine and rifampicin, both the peak plasma concentration and the area under the curve of nifedipine decreased markedly to about 40% of those without rifampicin. The findings suggest that rifampicin may increase the elimination of nifedipine, presumably by induction of its hepatic metabolism. Nisoldipine, another calcium antagonist, also failed to lower the patient's blood pressure, when given in combination with rifampicin. Taken together, these findings indicate that more caution should be urged when calcium antagonist is prescribed along with rifampicin.

Objective: To study the effect of interleukin (IL)-4 and IL-10 on nitric oxide (NO) production by macrophages.¶Materials and Methods: Elicited or resident peritoneal macrophages (PMO) and a macrophage cell line Raw264.7 were primed by IL-4 or IL-10 for 6 hours, and were further incubated in the presence of interferon (IFN)-γ and/or lipopolysaccharide (LPS) for 48 hours. NO2 - accumulation in the supernatant of cultured cells was used as an indicator of NO production and was determined by the standard Griess reaction adapted for microplates. The amount of tumor necrosis factor (TNF)-α in the culture supernatants was determined with a commercially available ELISA kit. The absorbance was measured at 450 nm with a microplate photometer.¶Results: IL-4 inhibited NO production by murine macrophages of different sources and the macrophage cell line Raw264.7. In contrast, different macrophage populations showed differential responses to IL-10. After stimulation with LPS or IFN-γ, IL-10 suppressed NO production by elicited PMO but enhanced NO production by resident PMO or by Raw264.7. Both IL-4 and IL-10 inhibited the production of TNF-α, which has been shown to play a crucial role in NO production. In the presence or the absence of blocking antibody to TNF-α, IL-10 always enhanced NO production by resident PMO. This result suggests that the inhibition of TNF-α production and the enhancement of NO production by resident PMO stimulated with IL-10 are independent, coexisting events.¶Conclusions: Factors other than TNF-α have been suspected to influence NO production by macrophages, and this study indicates that IL-10 may be a candidate cytokine for resident PMO.

Objective To analyze the Th1/Th2 balance of peripheral Th cells in patients with systemic lupus erythematosus (SLE). Methods The Th1:Th2 ratio was analyzed in 3 groups: SLE without proteinuria (group I; n = 23), SLE with proteinuria (group II; n = 31), and normal controls (group III; n = 24). Group II patients who had undergone renal biopsy were classified into 3 subgroups based on their renal histopathologic findings. The intracellular cytokine detection method with flow cytometry was used to quantitate Th1 and Th2 cells. Results There was no difference in the mean Th1:Th2 ratio between SLE patients (groups I and II) and healthy controls (group III). However, the mean value in group II was significantly higher than those in groups I and III. Moreover, within group II, the mean value in SLE patients who had diffuse proliferative lupus nephritis (World Health Organization class IV) was especially high. Conclusion Although SLE has been considered to be a disease in which Th2 cells predominate, the Th1/Th2 balance of peripheral Th cells in SLE patients in the present study did not show a predominance of these cells. In contrast, among SLE patients with WHO class IV lupus nephritis, there was a strong predominance of Th1.

Levels of serum granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with various leukocyte disorders were estimated by enzyme-linked immunosorbent assay (ELISA). Some cases of acute myelogenous leukemia and aplastic anemia showed elevated serum levels of G-CSF and/or GM-CSF, whereas almost all of 23 healthy controls showed G-CSF and GM-CSF levels lower than 100 pg/ml. High levels of both types of CSF were noted in patients with granulocytosis due to infection. These levels became lower after resolution of the infection. Daily changes in serum CSF levels were also examined in a patient with autoimmune neutropenia, and it was found that the peripheral neutrophilic granulocyte count changed almost in parallel with the serum G-CSF level but not with GM-CSF, following the pattern with a delay of about 4-5 h, suggesting the possibility that G-CSF mainly regulates peripheral neutrophil circulation.

Plasma renin activity (PRA) and urinary electrolyte excretion were measured in 137 healthy children aged 6 to 14 years. Plasma aldosterone concentration (PAC) was measured in 52 of the children. Nocturnal 12-hour urine was collected in 110 of the children. Spot urine was collected on two occasions, once just before lying down, once after 90-min supine rest in another 27. Na/K ratio and fractional Na excretion rate (FENa) in 12-hour urine showed a significant inverse correlation with PRA or PAC. Na excretion (mmol/min, mmol/mmol creatinine), Na/K ratio and FENa in the spot urine following 90 min in a supine position showed a significant inverse correlation with PRA or PAC, but they failed to show a significant relationship to PRA or PAC in the spot urine preceding supine rest. A spot urine after 90 min in the supine position is collected easily and hence most appropriate to study the relationship between Na excretion and PRA or PAC clinically.