Development of eosinophilic granulomatosis with polyangiitis during the clinical course of microscopic polyangiitis: A case report

Rationale: Eosinophilic granulomatosis with polyangiitis (EGPA) is belongs to the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) subgroups. EGPA, unlike other subgroups of AAV, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis, has the unique feature that both ANCA and eosinophilic inflammation are involved in its pathogenesis. Although AAV often relapses, there are currently no reports of EGPA developing during other subgroups of AAV. Herein, we document a case of EGPA that developed during the clinical course of MPA.Patient concerns: A 61-year-old Japanese woman was diagnosed with MPA based on interstitial lung disease and myeloperoxidase-ANCA positivity. After starting immunosuppression therapy, including prednisolone and tacrolimus, she was expected to achieve clinical remission. Nonetheless, she occasionally experienced MPA relapse, which required an increased prednisolone dose, rituximab, intravenous cyclophosphamide, and plasma exchange. Three years after MPA onset, she developed renal amyloidosis; thus, subcutaneous tocilizumab was added to her regimen. Following clinical remission, the administration interval of her subcutaneous tocilizumab therapy was extended and immunosuppressants were discontinued. She then developed bronchial asthma and mild eosinophilia (eosinophilic count: ~1000/μL). Further, a year later, she underwent total hip replacement using a titanium implant. Subsequently, she developed abnormal sensation in both hands, numbness, and muscle weakness, as well as palpable purpura and massive eosinophilia (eosinophilic count: ~8500/μL).Diagnosis: We diagnosed the patient with EGPA based on 5 items (asthma, multiple mononeuropathies, sinus abnormality, and extravascular eosinophils) of the 1990 American College of Rheumatology classification criteria.Interventions: We administered 400 mg/kg intravenous immunoglobulin for 5 consecutive days, 300 mg mepolizumab subcutaneously every 4 weeks, and 40 mg/day prednisolone following pulsed methylprednisolone therapy (1000 mg/day for 3 consecutive days).Outcomes: After these treatments, the patient’s symptoms improved, and eosinophilic count and inflammatory markers declined.Lessons: The present case suggests that EGPA can be induced by the development of eosinophilic inflammation in other subgroups of AAV.Abbreviations: AAV = ANCA-associated vasculitis, ANCA = antineutrophil cytoplasmic autoantibody, CCL = chemokine (C–C motif) ligands, CRP = C-reactive protein, EGPA = eosinophilic granulomatosis with polyangiitis, IL = interleukin, ILC2 = group 2 innate lymphoid cells, ILD = interstitial lung disease, MPA = microscopic polyangiitis, MPO = myeloperoxidase, mPSL = methylprednisolone, PSL = prednisolone, TAC = tacrolimus, TCZ = tocilizumab, Th2 = T helper 2

Infectious Pneumonia and Lower Airway Microorganisms in Patients with Rheumatoid Arthritis

The relationship between microorganisms present in the lower respiratory tract and the subsequent incidence of pneumonia in patients with rheumatoid arthritis is unclear. A retrospective cohort study was designed to include a total of 121 patients with rheumatoid arthritis who underwent bronchoscopy at three hospitals between January 2008 and December 2017. Data on patient characteristics, microorganisms detected by bronchoscopy, and subsequent incidences of pneumonia were obtained from electronic medical records. Patients were divided into groups based on the microorganisms isolated from the lower respiratory tract. The cumulative incidence of pneumonia was assessed using the Kaplan–Meier method, and decision tree analysis was performed to analyze the relation between the presence of microorganisms and the occurrence of pneumonia. The most frequently isolated microbes were Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae. Patients whose samples tested negative for bacteria or positive for normal oral flora were included in the control group. The rate of the subsequent incidence of pneumonia was higher in the P. aeruginosa group than in the control group (p = 0.026), and decision tree analysis suggested that P. aeruginosa and patient performance status were two important factors for predicting the incidence of pneumonia. In patients with rheumatoid arthritis, the presence of P. aeruginosa in the lower respiratory tract was associated with the subsequent incidence of pneumonia

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

Background and purposeThe Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] https://doi.org/10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine.MethodsMembers of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members.ResultsA total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs.ConclusionsBased on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals

Fluorosulfide La2+xSr1−xF4+xS2 with Triple-fluorite Layer Enabling Interstitial Fluoride-ion Conduction

Fluoride-ion conducting solid materials are applicable as solid electrolytes for sensing devices and next generation rechargeable batteries. Most of the previously reported materials have limited to the single-anion compounds such as fluorite-type, tysonite-type, and perovskite-type structures. These are suffered from further improvements by crystal structure modification which derives a paradigm shift in the material tailoring. Fluoride and sulfide ions prefer respective coordination environments because of the different ionic radii and electronegativity. This feature implies that fluorosulfide mixed-anion compounds have potential to form anion-ordering crystal structures with new fluoride-ion conducting layers. Herein, we have found that the fluorosulfide La2+xSr1−xF4+xS2 exhibits fluoride ion conduction. The presence of multiple anions results in the formation of anion-ordering two-dimensional crystal lattice with triple fluorite layers, which cannot be realized for metal fluorides. Sulfide ions in the crystal structure increases the number of interstitial sites of fluoride ions, forming fluoride ion conduction pathway

A novel highly quantitative and reproducible assay for the detection of anti-SARS-CoV-2 IgG and IgM antibodies

The quantitative range and reproducibility of current serological tests for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are not optimized. Herein, we developed a diagnostic test that detects SARS-CoV-2 IgG and IgM with high quantitativeness and reproducibility and low interference. The system was based on the high-sensitivity chemiluminescence enzyme immunoassay (HISCL) platform and detects IgG and IgM specific to SARS-CoV-2 spike and nucleocapsid proteins. Quantification accuracy and reproducibility were evaluated using serially diluted samples from 60 SARS-CoV-2-infected patients. Assay performance was evaluated using serum samples from the SARS-CoV-2-infected patients and 500 SARS-CoV-2-negative serum samples collected before the emergence of SARS-CoV-2. The system showed high quantification accuracy (range, 102), high reproducibility (within 5%), and no cross-reaction between SARS1- and MERS-S proteins. Detection accuracy was 98.3% and 93.3% for IgG and IgM against spike proteins and 100% and 71.7% for IgG and IgM against nucleocapsid proteins, respectively. Mean antibody levels were > 10 times that in negative samples upon admission and > 100 times that at convalescent periods. Clinical severity upon admission was not correlated with IgG or IgM levels. This highly quantitative, reproducible assay system with high clinical performance may help analyze temporal serological/immunological profiles of SARS-CoV-2 infection and SARS-CoV-2 vaccine effectiveness

短期間のうちにコルチゾールの自律的分泌能が明確となった副腎偶発腫瘍の一例

A 57-year-old woman was admitted to the hospital for the further evaluation of a left adrenal incidentaloma measuring 45 mm x 33 mm. She had no signs of the clinical manifestation of hypercortisolism. An endocrine evaluation revealed that her ACTH level was normal and cortisol values were almost normal pattern excluding the value at 9 PM slightly rising, however, the cortisol was not completely suppressed by the overnight administration of 1 mg dexamethasone. These findings indicated that subtle abnormalities of the hypothalamo-pituitary-adrenal axis were present in this case. After 3 months, surprisingly, the ACTH was suppressed to low levels. Further hormonal investigations revealed that the cortisol level was normal but had an abnormal diurnal rhythm and was not suppressed completely by a 1 mg or an 8 mg overnight dexamethasone dose. Adrenal scintigraphy revealed positive uptake in the left adrenal tumor with no uptake in the right adrenal gland. The patient underwent a left laparoscopic adrenalectomy. Microscopically, the tumor displayed histopathological features in common with ACTH-independent macronodular adrenocortical hyperplasia , including clear cell predominance, a pattern of small compact nests in clear cell areas, and a cord-like arrangement of small compact cells. An in situ hybridization study demonstrated the hybridization signals for P-450scc, 3β-HSD, P-450c21, P-45011β, and P-45017αwhich were observed in the clear cells as well as compact cells, the compact cells being more intensely stained. This case indicates the ability of autonomous cortisol production to become clear during a very short term and a more detailed and careful short-time follow-up should be recommended in patients with adrenal incidentalomas.症例は57 歳，女性．45 ｍｍｘ 33 ｍｍの左副腎偶発腫瘍の精査目的で当科に入院となった．高コルチゾール血症による身体所見は認めず，内分泌学的検査では，コルチゾールの夜間９時の値が軽度上昇している以外は，ACTH，コルチゾール値ともほぼ正常で日内リズムも保たれていた．しかしデキサメサゾン1mg 抑制試験ではコルチゾールは完全には抑制されなかった．よってわずかな間脳下垂体副腎系の異常が示唆され，腫瘍径も4cm を超えており摘出も検討したが，患者さんは保存的経過観察を希望され手術は施行しなかった．ところが３ケ月後の血液検査でACTH 値は感度以下の低値で，コルチゾール基礎値は正常であるが，デキサメサゾン1mgまたは8mg 抑制試験でコルチゾールは完全に抑制されなかった．アドステロール副腎シンチグラフィー検査では左副腎腫瘍に高集積を認め，右副腎には集積を認めなかった．そこで今回患者さんの同意を得て腹腔鏡下で左副腎摘出術を施行した．摘出副腎腫瘍は光顕像ではACTH-independent macronodularadrenocortical hyperplasia (AIMAH)の組織像であり，in situ hybridization studyではcompact cellにより強いP-450scc, 3β-HSD，P-450c21，P-45011βそしてP-45017αのシグナルが認めた．本症例は短期間のうちにコルチゾールの自律的分泌能が明確となった副腎偶発腫瘍の一例であり，より注意深い，詳細な，短期間のうちの内分泌学的経過観察が副腎偶発腫瘍に対して必要であることが示唆された

A Case of Adrenal Incidentaloma in which Autonomous Cortisol Production to become Clear during a Very Short Term

A 57-year-old woman was admitted to the hospital for the further evaluation of a left adrenal incidentaloma measuring 45 mm x 33 mm. She had no signs of the clinical manifestation of hypercortisolism. An endocrine evaluation revealed that her ACTH level was normal and cortisol values were almost normal pattern excluding the value at 9 PM slightly rising, however, the cortisol was not completely suppressed by the overnight administration of 1 mg dexamethasone. These findings indicated that subtle abnormalities of the hypothalamo-pituitary-adrenal axis were present in this case. After 3 months, surprisingly, the ACTH was suppressed to low levels. Further hormonal investigations revealed that the cortisol level was normal but had an abnormal diurnal rhythm and was not suppressed completely by a 1 mg or an 8 mg overnight dexamethasone dose. Adrenal scintigraphy revealed positive uptake in the left adrenal tumor with no uptake in the right adrenal gland. The patient underwent a left laparoscopic adrenalectomy. Microscopically, the tumor displayed histopathological features in common with ACTH-independent macronodular adrenocortical hyperplasia , including clear cell predominance, a pattern of small compact nests in clear cell areas, and a cord-like arrangement of small compact cells. An in situ hybridization study demonstrated the hybridization signals for P-450scc, 3β-HSD, P-450c21, P-45011β, and P-45017αwhich were observed in the clear cells as well as compact cells, the compact cells being more intensely stained. This case indicates the ability of autonomous cortisol production to become clear during a very short term and a more detailed and careful short-time follow-up should be recommended in patients with adrenal incidentalomas.症例は57 歳，女性．45 ｍｍｘ 33 ｍｍの左副腎偶発腫瘍の精査目的で当科に入院となった．高コルチゾール血症による身体所見は認めず，内分泌学的検査では，コルチゾールの夜間９時の値が軽度上昇している以外は，ACTH，コルチゾール値ともほぼ正常で日内リズムも保たれていた．しかしデキサメサゾン1mg 抑制試験ではコルチゾールは完全には抑制されなかった．よってわずかな間脳下垂体副腎系の異常が示唆され，腫瘍径も4cm を超えており摘出も検討したが，患者さんは保存的経過観察を希望され手術は施行しなかった．ところが３ケ月後の血液検査でACTH 値は感度以下の低値で，コルチゾール基礎値は正常であるが，デキサメサゾン1mgまたは8mg 抑制試験でコルチゾールは完全に抑制されなかった．アドステロール副腎シンチグラフィー検査では左副腎腫瘍に高集積を認め，右副腎には集積を認めなかった．そこで今回患者さんの同意を得て腹腔鏡下で左副腎摘出術を施行した．摘出副腎腫瘍は光顕像ではACTH-independent macronodularadrenocortical hyperplasia (AIMAH)の組織像であり，in situ hybridization studyではcompact cellにより強いP-450scc, 3β-HSD，P-450c21，P-45011βそしてP-45017αのシグナルが認めた．本症例は短期間のうちにコルチゾールの自律的分泌能が明確となった副腎偶発腫瘍の一例であり，より注意深い，詳細な，短期間のうちの内分泌学的経過観察が副腎偶発腫瘍に対して必要であることが示唆された

Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin

Sterol-regulatory element binding protein-1c (SREBP-1c) is a transcription factor that controls lipogenesis in the liver. Hepatic SREBP-1c is nutritionally regulated, and its sustained activation causes hepatic steatosis and insulin resistance. Although regulation of SREBP-1c is known to occur at the transcriptional level, the precise mechanism by which insulin signaling activates SREBP-1c promoter remains to be elucidated. Here we show that protein kinase C beta (PKCbeta) is a key mediator of insulin-mediated activation of hepatic SREBP-1c and its target lipogenic genes. Activation of SREBP-1c in the liver of refed mice was suppressed by either adenoviral RNAi-mediated knockdown or dietary administration of a specific inhibitor of protein kinase C beta. The effect of PKCbeta inhibition was cancelled in insulin depletion by streptozotocin (STZ) treatment of mice. Promoter analysis indicated that PKCbeta activates SREBP-1c promoter through replacement of Sp3 by Sp1 for binding to the GC box in the sterol regulatory element (SRE) complex, a key cis-element of SREBP-1c promoter. Knockdown of Sp proteins demonstrated that Sp3 and Sp1 play reciprocally negative and positive roles in nutritional regulation of SREBP-1c, respectively. This new understanding of PKCbeta involvement in nutritional regulation of SREBP-1c activation provides a new aspect of PKCbeta inhibition as a potential therapeutic target for diabetic complications