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Hereditary angioedema (HAE) is a potentially life-threatening rare disease, which is mainly caused by the deficiency or dysfunction of C1-esterase inhibitor, and characterized by spontaneous, recurrent episodes of edema in various parts of the body including internal organs and the laryngeal area. Delayed diagnosis and treatment increase the burdens and risks of this condition. The current study aimed to understand the burden of illness for HAE patients in Japan before and after diagnosis through a patient reported outcome survey. A survey instrument was distributed to 121 adult patients with HAE by a patient organization via HAE treating physicians between July and November in 2016. Seventy patients (57.9%) returned the questionnaire. Patients reported high levels of medical resource utilization, including emergency procedures and services. Episodes of receiving laparotomy were somewhat less after diagnosis with HAE than before, but no apparent difference in episodes of tracheotomy between before and after the diagnosis. The economic burden, including direct and indirect medical costs, was highest before diagnosis, but still perceived as substantial after diagnosis. Patients reported disruption of work and school life, with 40% reporting that they miss 10 or more days from work or education per year. Sixty percent of patients reported that HAE affected their daily activities. We concluded that HAE is associated with considerable physical, social, economic and psycho-social burdens even after diagnosis, and that higher attack frequency is associated with a heavy disease burden for patients in Japan.

Background The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs. Methods A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016–2017. Responses were collected from 70 patients (57.9%) and subjected to analysis. Results The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min–max, 0–53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3–73) and at diagnosis 32.8 years (0–73). Patients reported an average of 15.7 (0–100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0–200) before diagnosis, but these declined to 4.3 (0–50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect. Conclusions There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.

Hereditary angioedema caused by C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare autosomal dominant disease. Primary care physicians sometimes face difficulties in diagnosing HAE-C1-INH owing to fluctuations in C1-INH function levels influenced by blood sampling conditions. International major guidelines do not stipulate a cut-off value of C1-INH function for the diagnosis. We aimed to explore the distribution of C1-INH function levels in patients with HAE-C1-INH and elucidate the influence of blood sampling conditions using healthy volunteers' samples to confirm the cut-off value of C1-INH function. In 48 patients with HAE-C1-INH who visited the Juntendo University Hospital in Japan between 2013 and 2019, C1-INH function levels were evaluated for 160 samples during symptom-free periods and 147 samples during an acute attack. Fluctuations of C1-INH function level were also evaluated for 8 healthy volunteers, wherein the samples were divided into 3 groups according to different sampling conditions. C1- INH function levels in all patients with HAE-C1-INH were found to be < 50%. The average C1- INH function level in healthy volunteers measured soon after blood collection in an appropriate sampling condition was 77% (61-92%) with some having lower C1-INH function levels than the reference value. C1-INH function levels fluctuated unstably in inappropriate sampling conditions. In conclusion, we can confirm that a < 50% C1-INH function level can be used as the diagnostic cut-off value for HAE-C1-INH. Moreover, it is necessary to repeat measurements of C1-INH function level in appropriate blood sampling conditions to accurately diagnose HAE-C1-INH.

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare disease, which induces an acute attack of angioedema mediated by bradykinin. HAE-C1-INH can cause serious abdominal pain when severe edema develops in the gastrointestinal tract. However, because it takes a long time, 13.8 years on average in Japan, from the occurrence of the initial symptom to the diagnosis due to low awareness of the disease, undiagnosed HAE-C1-INH patients sometimes undergo unnecessary surgical procedures for severe abdominal pain. We herein present a 56-year-old patient with HAE-C1-INH, who underwent numerous abdominal operations. He frequently needed hospitalization with the administration of opioid due to severe abdominal pain. However, after he was accurately diagnosed with HAE-C1-INH at 55 years of age, he could start self-administration for an acute attack with icatibant, a selective bradykinin B2 receptor antagonist. Consequently, he did not need hospitalizing for ten months after the beginning of the treatment. A series of an accurate diagnosis and appropriate treatment for HAE-C1-INH improved his quality of life. Thus, HAE-C1-INH should be considered, when we meet patients with unidentified recurrent abdominal pain. This case highlights significance of an early diagnosis and appropriate treatment for HAE-C1-INH.

Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B2 receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies.

Background With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long‐term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once‐daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients. Methods APeX‐J is a phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group, 3‐part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run‐in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert‐confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs., APeX‐J is a phase 3, placebo‐controlled trial conducted in Japan to assess the efficacy and safety of oral berotralstat in patients with HAE. Patients were randomized 1:1:1 to receive once‐daily berotralstat 110 mg, berotralstat 150 mg, or placebo. Berotralstat 150 mg significantly reduced the frequency of HAE attacks compared with placebo, supporting its use as a prophylactic therapy. Abbreviation: HAE, hereditary angioedema.

Recently, postmortem imaging is sometimes used as an alternative to conventional autopsy. However, there are few case reports of postmortem imaging of dialysis patients. Here, we report a fatal case of gas gangrene involving a 76-year-old man who underwent dialysis. He died suddenly before a diagnosis could be established. Immediately after his death, postmortem computed tomography (PMCT) revealed gas accumulation in his right upper extremity and ascending aorta. Gas gangrene progresses rapidly and may sometimes result in sudden death before it is diagnosed. In this case, PMCT findings were useful to diagnose gas gangrene. Intravascular gas is a common finding on PMCT and is generally caused by cardiopulmonary resuscitation and decomposition. However, the detection of gas in the ascending aorta by PMCT was not described previously. Moreover, Gram stain and culture of the exudate showed anaerobic Gram-positive bacilli which suggested that the gas generation in the blood was caused by Clostridia species. To the best our knowledge, this is the first report of a dialysis patient whose cause of death was determined as gas gangrene using PMCT.

Ceftriaxone-associated biliary pseudolithiasis is common among children; however, there are only a few reports of pseudolithiasis in adult patients on HD. This retrospective cohort study included 278 adult patients on ceftriaxone therapy from 1 February 2016 to 1 September 2018. Pseudolithiasis was defined as a new development of sludge or stones in the gallbladder within 60 days of ceftriaxone therapy. After excluding patients with preexisting gallstones and a history of cholecystectomy, 113 patients on maintenance HD, and another 98 patients were enrolled as the HD and control group, respectively. Thirteen patients developed pseudolithiasis. Its incidence was significantly higher in the HD group than that in the control group. Multivariate logistic regression analyses showed that development of pseudolithiasis was significantly associated with HD and ceftriaxone dose. Therefore, HD in patients receiving ceftriaxone therapy appears to be associated with a risk of pseudolithiasis. These findings highlight the need for careful follow-up.

Purpose Dipeptidyl peptidase-4 inhibitors, including linagliptin, prevent inflammation. However, the in vitro effects of linagliptin are unclear. Moreover, although linagliptin inhibits lipopolysaccharide (LPS)-induced inflammation, the anti-inflammatory effects of linagliptin in this context are not concentration-dependent. In the absence of LPS-binding protein (LBP), the pro-inflammatory effects of LPS involve pathways other than the Toll-like receptor (TLR) 4 pathway. Here, we aimed to determine the anti-inflammatory mechanisms of linagliptin in an experimental model in which LBP was added to the medium. Methods Human U937 monocytes were cultured at 1 × 106 cells/mL in Roswell Park Memorial Institute medium and differentiated into macrophages using phorbol myristate acetate. All processes were carried out in medium containing 10% fetal bovine serum (FBS). After 48 hrs of culture, we replaced the medium and pretreated the cells with 100, 250, 500, or 2500 nM linagliptin for 1 hr. We exchanged the medium again, and the cells were treated with 1 ng/mL LPS with or without 100, 250, 500, or 2500 nM linagliptin. Interleukin (IL)-6 and LBP in the supernatant, nuclear factor (NF)-κB/p65 in the nucleus, and reactive oxygen species (ROS) in the cells, as important markers of the mechanism of inflammation induction by LPS, were measured using enzyme-linked immunosorbent assay kits. Results Linagliptin significantly prevented LPS-stimulated IL-6 production and intranuclear NF-κB/p65 levels in a concentration-dependent manner. LPS-induced intracellular ROS levels were significantly decreased by linagliptin at all concentrations. LBP levels were markedly higher in FBS-containing medium than in medium without FBS. However, LBP levels did not change following administration of linagliptin and/or LPS. Conclusion Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment in the context of LPS-induced pro-inflammatory responses. Thus, our findings suggested that linagliptin induced two different mechanisms to repress inflammation, i.e., TLR4-dependent and -independent mechanisms.

Hiroshi Saito,1 Yuya Nakamura,2,3 Masahiro Inagaki,2,4 Shiho Yamadera,5 Hideo Misawa,2,3 Naoki Sato,2,6 Tatsunori Oguchi,2 Takae Inagaki,7 Yuya Tsuji,2 Mayumi Tsuji,2 Isao Ohsawa,3 Hiromichi Gotoh,3 Yuji Kiuchi2 1JA Hiroshima Genneral Hospital, Hatsukaichi City, Hiroshima, Japan; 2Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan; 3Saiyu Soka Hospital, Soka City, Saitama, Japan; 4Faculty of Arts and Sciences at Fujiyoshida, Showa University, Fujiyoshida City, Yamanashi, Japan; 5Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan; 6Department of Research Center, Tanabe Pharmacy Inc., Chuo-ku, Tokyo, Japan; 7Graduate School of Nursing and Rehabilitation Science, Yokohama City, Kanagawa, JapanCorrespondence: Yuya Nakamura Email y.nakamura@med.showa-u.ac.jpPurpose: Lipopolysaccharides (LPS) induce inflammation by binding to the Toll-like receptor (TLR) 4 complex, including LPS-binding protein (LBP). The anti-inflammatory effects of linagliptin in LPS-induced inflammation in the TLR4-independent pathway have not been examined before. We examined the anti-inflammatory effects of linagliptin in the TLR4- and the LBP-independent pathway.Methods: U937 cells were cultured in the medium supplemented with 10% fetal bovine serum (FBS) and treated with 100 nM phorbol myristate acetate for 48 h. Cells were then left untreated or were treated with 10 μg/mL anti-TLR4 antibodies alone or in combination with linagliptin for 1 h in media supplemented with or without 10% FBS. The cells were divided into 5 groups: a) control cells (untreated) b) cells treated with LPS c) cells treated with 10 μg/mL anti-TLR4 antibodies d) cells treated with LPS and 10 μg/mL anti-TLR4 antibodies and e) cells treated with LPS, 10 μg/mL anti-TLR4 antibodies, and linagliptin. The LPS concentrations used were 50 pg/mL or 100 pg/mL for cells treated in the presence of 10% FBS and 100 pg/mL or 1 μg/mL for cells treated in the absence of FBS. Linagliptin concentrations of 1 nM, 10 nM, and 100 nM were used for treatment. The supernatants were analyzed for interleukin (IL)-6 production after 24 h of various treatments.Results: LPS increased IL-6 production compared to the untreated control cells, and anti-TLR4 antibody suppressed LPS-induced increased IL-6 levels. Linagliptin suppressed LPS-induced IL-6 production in a concentration-dependent manner in the presence of FBS. However, only 100 nM linagliptin could suppress LPS-induced IL-6 production in the absence of FBS.Conclusion: Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment after LPS induction in an experimental model of TLR4 inhibition by anti-TLR4 antibodies. Our results showed that linagliptin may inhibit inflammation through multiple mechanisms centered around the TLR-4-mediated pathway.Keywords: lipopolysaccharide, U937 cells, fetal bovine serum, anti- toll-like receptor 4 antibody, interleukin-6

Hereditary angioedema due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) induces an acute attack of angioedema. In 2018, icatibant available for self-possession and subcutaneous self-administration was licensed for on-demand treatment in addition to intravenous C1-INH administration in Japan. We retrospectively evaluated the percentage of attacks in critical parts at emergency room (ER) visits and the time until visiting ER for C1-INH administration before and after the initial prescription of icatibant. The percentage of attacks in critical parts at ER visits before the prescription was 69.2%, but that was 80.0% when patients visited ER for additional C1-INH administration after the self-administration of icatibant. The time from the onset of an acute attack to visiting ER for the additional treatment after the self-administration of icatibant significantly increased from 6.2 h to 19.2 h (p < 0.001). Icatibant, therefore, promoted the patients' behavior modification associated with ER visits for C1-INH administration during an acute attack of HAE-C1-INH.

A 42-year-old Japanese man with hereditary angioedema suffered accidental trauma to his jaw in Shizuoka Prefecture, Japan, which gradually caused facial edema. Since plasma-derived human C1 inhibitor (pdh C1-INH) was unavailable, he had to be transferred to Juntendo University Hospital in Tokyo. Due to his severe edema, he suffered asphyxiation leading to cardiopulmonary arrest upon arrival. The patient was resuscitated and promptly treated with pdh C1-INH. In Japan, the self-administration of pdh C1-INH is not allowed, and every prefecture does not always possess stocks of pdh C1-INH. This case emphasizes the need for urgent improvements in treatment availability in Japan.

Background: Hereditary angioedema (HAE) is a rare but life-threatening condition. HAE types I and II (HAE-1/2) result from C1-inhibitor (C1–INH) deficiency. However, recent genetic analysis has established a new type of HAE with normal C1–INH (HAEnC1-INH). The mutations of factor XII, plasminogen, angiopoietin 1, and kininogen 1 genes may be the cause of HAEnC1-INH. Nevertheless, other causative molecules (HAE-unknown) may be involved. The Japanese therapeutic environment for HAE has been improving owing to the self-subcutaneous injection of icatibant, which was approved for the treatment of acute attack and enables early therapy. Erythema marginatum (EM) is a visible prodromal symptom which occasionally occurs prior to an angioedema attack; hence, recognizing the risk of an acute attack is important for early treatment. However, the detailed characteristics of EM remain unclear. In this study, we first investigated the clinical manifestations of EM in Japanese patients with HAE. Methods: A 20-point survey was developed and distributed to 40 physicians to gather clinical data on EM from patients with HAE. Results: Data on 68 patients with HAE (58 patients with HAE-1/2 and 10 patients with HAE-unknown) were collected. Of the patients with HAE-1/2, 53.4% experienced EM, whereas 43.1% did not. The forearm was the most frequent area of EM (64.5%), followed by the abdomen (29.0%) and upper arm and precordium (19.3%). Of the HAE-1/2 patients with EM, 41.9% always had angioedema following EM, while 29.0% always had colocalization of EM with angioedema. Moreover, 3.2% showed a correlation between the awareness of EM and severity of an angioedema attack. In 60.9% of HAE-1/2 patients with EM, the interval between the awareness of EM and appearance of angioedema was

This document summarizes the aims of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence (ACAREs) and elaborates the requirements that ACAREs must fulfill to become certified. It also provides (see Appendix S1) background information on GA2LEN and HAEi, including HAEi member organizations and regional patient advocates, on why we need an Angioedema Center of Reference and Excellence (ACARE) program and network, and on the accreditation and certification process, governance and funding, and on the interaction with other GA2LEN networks of centers of reference and excellence. The protocols, aims, requirements, and provisions related to becoming a certified CARE are based on (a) the experience of the GA2LEN UCARE network and (b) input from angioedema patients, general practitioners, and angioedema specialists.

Background and Aims Diffuse idiopathic skeletal hyperostosis (DISH) is an idiopathic degenerative disease characterized by ossification of spinal ligaments and entheses, especially in the anterior longitudinal ligament. The ankylosed spine is prone to fracture with minor trauma and may result in spinal cord injury. It is usually asymptomatic and often diagnosed incidentally by computed tomography or other imaging methods. Several reports have revealed DISH as a risk factor for stroke, cardiovascular disease, and metabolic disorders, such as diabetes mellitus, hyperinsulinemia, obesity, dyslipidemia, and hyperuricemia. However, there are few reports of DISH in patients with end stage kidney disease (ESKD) requiring hemodialysis. Epidemiology, etiology and risk factors of DISH in patients with ESKD are unknown. We aimed to examine the prevalence and predictors of DISH in maintenance hemodialysis patients. Method This was a case-control study using patients who received maintenance hemodialysis in our hospital in December 2018. The prevalence of DISH at enrollment was evaluated according to Resnick and Niwayama criteria by computed tomography (CT). The criteria is defined as follows: (1) Flowing ossification along the anterolateral aspect of at least four contiguous vertebral bodies, (2) Relative preservation of intervertebral disc height in the involved segment, (3) Absence of apophyseal joint bony ankylosis and sacroiliac joint erosion. We excluded patients who could not receive chest CT or with a history of thoracic spine surgery. Fisher exact tests were used to evaluate the relationships between categorical variables, and Kruskal-Wallis or Mann-Whitney U tests were used to evaluate continuous variables. We performed logistic regression analyses to identify variables that had a statistically significant association with DISH, as measured by the estimated odds ratio (OR) with the 95% confidence interval (CI). Results A total of 395 consecutive patients were treated with maintenance hemodialysis in our hospital in December 2018. After excluding 4 patients who could not receive chest CT and 2 patients with a history of thoracic spine surgery, the remaining 389 patients were analyzed. The median age was 70 years, and 61.2% of patients were men. One hundred and twenty-three (31.6%) patients were diagnosed with DISH. We assigned them to the DISH group and other 266 patients to the control group. The patients with DISH were significantly more likely to have advanced age, male sex, high body weight, high bone mineral density, prior vertebral fracture, and diabetic nephropathy. Multivariate analysis showed that having DISH was significantly associated with advanced age (OR 1.06, 95%CI 1.03-1.09, P Conclusion The prevalence of DISH in maintenance hemodialysis patients was high. Advanced age, male sex, high body weight, high bone mineral density, prior vertebral fracture, and diabetic nephropathy were identified as a risk factor for DISH. Physicians involved in hemodialysis treatment should be aware of the existence of DISH as one of the comorbidities in the elderly ESKD patients.

Background and Aims There are several reports that the initial (within one year) failure of vascular access (VA) is 2–53% in several countries. Malnutrition alone, inflammation alone, and anemia alone are factors that have a well-known relationship to VA failure. We believe that the relationship of these risk factors to VA failure is a complex one. Therefore, we evaluated whether the addition of these factors had a synergistic impact on VA failure. Method This longitudinal cohort study sought to confirm the effects of malnutrition, inflammation, and anemia on VA failure. We included 177 patients with chronic kidney disease (CKD) with first-time arteriovenous fistulas who were treated from January 2013 to December 2017. VA failure was defined as a new onset of VA obstruction or the need for percutaneous transluminal angioplasty. Albumin (Alb), C-reactive protein (CRP), and hemoglobin (Hb) were studied as indicators for malnutrition, inflammation, and anemia, respectively. Each highest (CRP) or lowest (Alb and Hb) interquartile range (IQR) group was assigned 1 point (as a risk score). The cumulative VA failure rate was analyzed by the Kaplan-Meier method, which stratified the study cohort into four groups according to the risk scores (0–3). We assessed whether the lowest IQR group of Hb and Alb, and the highest IQR group of CRP were associated with VA failure. To determine this, we used a univariable Cox proportional hazards regression analysis to calculate the hazard ratio (HR) and its 95% confidence interval (CI). A multivariable Cox proportional hazards regression analysis was used to evaluate the association between the risk score and VA failure, with adjustment for age, sex, presence or absence of diabetes mellitus, value of calcium phosphate products, preoperative vein diameter, and intraoperative vascular assessment scores. Results The average observational period was 1.6±1.4 years. The incidence of VA failure was 30.5% (54 patients). Cumulative VA failure was significantly higher in patients who had more than two risk scores, as compared to the patients who did not have any risk score (Figure). The univariate Cox regression analysis showed that Alb, CRP, and Hb were significantly associated with VA failure (HR, 2.00; 95% CI, 1.08–3.71 for Alb and HR, 2.21; 95% CI, 1.15–4.13 for CRP and HR, 1.96; 95% CI, 1.02–3.63 for Hb), respectively. The presence of more than two risk scores was significantly associated with VA failure (HR, 4.68; 95% CI, 1.07–18.5 for the patients with two risk scores and HR, 4.72; 95% CI, 1.32–17.2 for the patients with three risk scores). Conclusion Malnutrition, inflammation, and anemia independently and synergistically affect VA failure. In clinical settings, we need to be aware of the presence of malnutrition, inflammation, and anemia to better prevent VA failure.

Background: A patient’s motivation for consulting a physician is paramount to the first steps of achieving an early diagnosis of hereditary angioedema (HAE). Understanding what triggers this motivation can help in the design of strategies to increase the number of visits to a specialist physician following early symptoms of HAE. The aim of the present study was to identify the reasons that led patients to seek the opinion of an HAE expert physician.

Objective The present study was designed to identify the clinical characteristics that permit the differential diagnosis of hereditary angioedema (HAE) and mast cell-mediated angioedema (Mast-AE) during the first consultation. Methods The medical histories and laboratory data of 46 patients with HAE and 41 patients with Mast-AE were compared. Results The average age of onset in the HAE group (19.8±9.0 years) was significantly lower than that in the Mast-AE group (35.2±12.0 years). The incidence of familial angioedema (AE) in the HAE group (73.9%) was significantly higher than that in the Mast-AE group (9.7%). The frequency of history of AE in the extremities, larynx, or gastrointestinal tract was significantly higher in the HAE group. The frequency of AE episodes of the lips and eyelids was significantly lower in the HAE group. The serum C4 concentration and CH50 titer were lower than the normal limit in 91.3% and 45.6% of the patients in the HAE group, respectively; in Mast-AE group the serum C4 concentration and CH50 titer were significantly lower than the normal limit in 4.8% and 0% of the patients, the difference between the two groups was statistically significant. A C1-inhibitor (C1-INH) activity level of

Background Hereditary angioedema (HAE) is an autosomal dominant disease caused by deficiency of C1 esterase inhibitor. Symptoms of HAE include edema, which can potentially cause suffocation. Some patients with HAE exhibit immunological abnormalities, which could prevent an accurate diagnosis. Low levels of complement components are characteristic of HAE and in other settings are thought to reduce elimination of apoptotic cells and immune complex (IC). Thus, we aimed to experimentally clarify the mechanism of immunological abnormalities using sera from HAE patients. Methods Serum samples from 18 patients with HAE were collected when free from angioedema attack and compared with normal human pooled sera (NHPS) from 20 healthy volunteers. Opsonization was measured as the rate of phagocytosis of apoptotic Jurkat cells by macrophages differentiated from THP-1 cells incubated with serum. IC solubilization in serum was analyzed by quantifying peroxidase released from a synthetic IC composed of peroxidase and anti-peroxidase antibodies. Anti-C1q antibody levels were detected using an enzyme-linked immunosorbent assay. Results Serological immunological abnormalities were detected in 12 patients. Opsonization in serum samples from each patient with HAE was lower than that in NHPS (∼20% versus 70%, respectively). The rate of IC solubilization was lower in serum from HAE patients than NHPS. Some patients had high serum anti-C1q antibody levels with increased serum IC levels. Conclusions Sera from patients with HAE exhibit anti-C1q antibodies, with a lower capacity for opsonization and IC solubilization. This may be associated with immunological abnormalities and should be investigated further to facilitate accurate diagnosis of HAE.

A correction to this paper has been published: https://doi.org/10.1007/s12328-021-01390-x

Background Many people have thyroid conditions that make them susceptible to hypothyroidism. If the foods they eat may interfere with the production of thyroid hormone, which can lead to development of serious hypothyroidism. The danger of health drinks should always be noted. Case presentation A 72-year-old Japanese woman was previously diagnosed with chronic lymphocytic thyroiditis caused by a goiter and had an elevated thyroid-stimulating hormone level (6.56 μIU/ml), a high anti-thyroid peroxidase antibody level (>600 IU/ml), and a high antithyroglobulin level (> 4000 IU/ml) but normal levels of free triiodothyronine (3.08 pg/ml) and thyroxine (1.18 ng/ml). She presented to our hospital with sudden-onset general malaise, edema, and hoarseness with an elevated thyroid-stimulating hormone (373.3 μIU/ml) level and very low triiodothyronine (

Cu/Zn-superoxide dismutase (Cu/Zn-SOD) is an enzyme that is ubiquitously present in the cytoplasm and causes dismutation of superoxide radicals, therefore Cu/Zn-SOD is primarily used as an antioxidant marker. Levels of Cu/Zn-SOD are higher in the serum of hemodialysis patients than in serum of healthy volunteers. The increase of serum Cu/Zn-SOD levels is related to the decrease of kidney function with aging and arteriosclerosis in hemodialysis patients. Moreover, infection, vascular puncture, and hemostasis may be related to the increase in serum Cu/Zn-SOD levels. As it is associated with numerous factors in hemodialysis patients, Cu/Zn-SOD may serve as a complex marker for arteriosclerosis, vascular, and inflammatory conditions. It is important to investigate various agents that decrease serum Cu/Zn-SOD levels to improve the life-span of hemodialysis patients.

Aim: To examine the effects of vitamin E-coated dialyzer on oxidative stress in vitro. Methods: A dialyzer with a synthetic polymer membrane (APS-11SA) and vitamin E-coated dialyzer (VPS-11SA) were connected to a blood tubing line, and U937 cells were circulated in the device. The circulating fluid was collected at 1, 2, 5, 10, 25, and 50 cycles, which are estimated numbers of passes through the dialyzer. Intracellular reactive oxygen species (ROS) production, malondialdehyde (MDA), and Cu/Zn-superoxide dismutase (SOD) were quantified. Results: Intracellular ROS production was increased in the first cycle by APS-11SA and was decreased throughout the experiment by VPS-11SA. Intracellular ROS production in the VPS-11SA device was lower, and MDA levels were decreased. MDA levels were lower during VPS-11SA processing than during APS-11SA processing. Cu/Zn-SOD levels remained unchanged. Conclusion: Our results highlight anti-oxidative-stress effects of a vitamin E-coated dialyzer.

Background Activities of daily living (ADL) in aged hemodialysis patients decrease by many factors as hemodialysis therapy, various disease-related complications and underlying disease for rehabilitation. But the correlation between low ADL and mortality remains unclear. We assessed the levels of ADL and effects of rehabilitation in hemodialysis patients with low ADL. Moreover, the association between the baseline functional independence measure (FIM) or rehabilitation treatment effects and all-cause mortality were investigated. Methods This prospective cohort study included 182 inpatients on maintenance hemodialysis, who underwent rehabilitation for a decline in ADL. Before and after initiating rehabilitation, ADL were assessed using FIM. Results The total baseline FIM was 65.1±26.9 (motor items: 39.5±18.7; cognitive items: 25.6±10.7). After rehabilitation, the total FIM increased to 77.1±33.1 (motor items: 50.9±24.4; cognitive items: 26.1±10.8). The baseline FIM, presence or absence of FIM increase, and albumin were significantly associated with mortality. Moreover, the mortality hazard ratio in patients with FIM ≤67 and no FIM increase was 20-fold significantly higher than that in patients with FIM ≥68 and FIM increase. The cognitive items and albumin were significantly associated with the rehabilitation effects in multivariate analysis. Conclusions Although the FIM decreased by half in hemodialysis patients, rehabilitation improved their FIM (particularly the motor items). The FIM was a novel predictive marker of 3-year mortality in these patients, and an increased FIM after rehabilitation resulted in better prognosis. Moreover, the effectiveness of rehabilitation may depend on maintaining cognitive functions.