Toho University Omori Medical Center

STUDY DESIGN: Tissues in the area of herniated lumbar discs were examined for inflammatory cytokines to elucidate the causes of sciatic pain in lumbar disc herniation. OBJECTIVES: To determine the role of inflammatory cytokines in the stimulation of sciatic pain in lumbar disc herniation. SUMMARY OF BACKGROUND DATA: It is postulated that in addition to mechanical compression of lumbar nerve roots and sensory root ganglia by herniated discs, there is a chemical stimulus to the production of sciatic leg pain. The exact mechanisms of chemical stimulation are not clearly defined. METHODS: During surgery, cases of lumbar disc herniation in 77 patients were classified macroscopically into protrusion, extrusion, and sequestration types. Tissues adjacent to nerve roots at the herniation were excised and analyzed biochemically and immunohistochemically for the presence of inflammatory cytokines and for the production of these cytokines and prostaglandin E2 in vitro. RESULTS: The homogenates of samples were analyzed for interleukin-1 alpha, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and granulocyte-macrophage colony stimulating factor, which were detectable. Most of the cytokine-producing cells were histiocytes, fibroblasts, or endothelial cells in extrusion and sequestration types, and chondrocytes in protrusion type. The secretion of these cytokines and prostaglandin E2 was decreased by the addition of betamethasone. The prostaglandin E2 production was dramatically enhanced by additional interleukin-1 alpha, but decreased by the addition of tumor necrosis factor-alpha. CONCLUSION: The results demonstrate that at the site of lumbar disc herniation, inflammatory cytokines such as interleukin-1 alpha are produced, which increases prostaglandin E2 production. Further studies are required to elucidate the role of inflammatory cytokines in causing sciatic pain.

OBJECTIVES: To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. METHODS: In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. RESULTS: 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. CONCLUSION: In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.

We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.

<h3>Background and Objectives</h3> The glymphatic system is a whole-brain perivascular network, which promotes CSF/interstitial fluid exchange. Alterations to this system may play a pivotal role in amyloid β (Aβ) accumulation. However, its involvement in Alzheimer disease (AD) pathogenesis is not fully understood. Here, we investigated the changes in noninvasive MRI measurements related to the perivascular network in patients with mild cognitive impairment (MCI) and AD. Additionally, we explored the associations of MRI measures with neuropsychological score, PET standardized uptake value ratio (SUVR), and Aβ deposition. <h3>Methods</h3> MRI measures, including perivascular space (PVS) volume fraction (PVSVF), fractional volume of free water in white matter (FW-WM), and index of diffusivity along the perivascular space (ALPS index) of patients with MCI, those with AD, and healthy controls from the Alzheimer9s Disease Neuroimaging Initiative database were compared. MRI measures were also correlated with the levels of CSF biomarkers, PET SUVR, and cognitive score in the combined subcohort of patients with MCI and AD. Statistical analyses were performed with age, sex, years of education, and <i>APOE</i> status as confounding factors. <h3>Results</h3> In total, 36 patients with AD, 44 patients with MCI, and 31 healthy controls were analyzed. Patients with AD had significantly higher total, WM, and basal ganglia PVSVF (Cohen <i>d</i> = 1.15–1.48; <i>p</i> &lt; 0.001) and FW-WM (Cohen <i>d</i> = 0.73; <i>p</i> &lt; 0.05) and a lower ALPS index (Cohen <i>d</i> = 0.63; <i>p</i> &lt; 0.05) than healthy controls. Meanwhile, the MCI group only showed significantly higher total (Cohen <i>d</i> = 0.99; <i>p</i> &lt; 0.05) and WM (Cohen <i>d</i> = 0.91; <i>p</i> &lt; 0.05) PVSVF. Low ALPS index was associated with lower CSF Aβ42 (<i>r</i>_<i>s</i> = 0.41, <i>p</i>_<i>fdr</i> = 0.026), FDG-PET uptake (<i>r</i>_<i>s</i> = 0.54, <i>p</i>_<i>fdr</i> &lt; 0.001), and worse multiple cognitive domain deficits. High FW-WM was also associated with lower CSF Aβ42 (<i>r</i>_<i>s</i> = −0.47, <i>p</i>_<i>fdr</i> = 0.021) and worse cognitive performances. <h3>Discussion</h3> Our study indicates that changes in PVS-related MRI parameters occur in MCI and AD, possibly due to impairment of the glymphatic system. We also report the associations between MRI parameters and Aβ deposition, neuronal change, and cognitive impairment in AD.

We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

BACKGROUND AND PURPOSE: The necessity for structural MRI is greater than ever to both diagnose AD in its early stage and objectively evaluate its progression. We propose a new VBM-based software program for automatic detection of early specific atrophy in AD. MATERIALS AND METHODS: A target VOI was determined by group comparison of 30 patients with very mild AD and 40 age-matched healthy controls by using SPM. Then this target VOI was incorporated into a newly developed automated software program independently running on a Windows PC for VBM by using SPM8 plus DARTEL. ROC analysis was performed for discrimination of 116 other patients with AD with very mild stage (n = 45), mild stage (n = 30) and moderate-to-advanced stages (n = 41) from 40 other age-matched healthy controls by using a z score map in the target VOI. RESULTS: Medial temporal structures involving the entire region of the entorhinal cortex, hippocampus, and amygdala showed significant atrophy in the patients with very mild AD and were determined as a target VOI. When we used the severity score of atrophy in this target VOI, 91.6%, 95.8%, and 98.2% accuracies were obtained in the very mild AD, mild AD, and moderate-to-severe AD groups, respectively. In the very mild AD group, a high specificity of 97.5% with a sensitivity of 86.4% was obtained, and age at onset of AD did not influence this accuracy. CONCLUSIONS: This software program with application of SPM8 plus DARTEL to VBM provides a high performance for AD diagnosis by using MRI.

Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder characterised by raised pulmonary artery pressures with pathological changes in small pulmonary arteries. Previous studies have shown that approximately 70% of familial PAH and also 11-40% of idiopathic PAH (IPAH) cases have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene. In addition, mutations in the activin receptor-like kinase 1 (ALK1) gene have been reported in PAH patients. Since both the BMPR2 and ALK1 belonging to the transforming growth factor (TGF)-beta superfamily are known to predispose to PAH, mutations in other genes of the TGF-beta/BMP signalling pathways may also predispose to PAH. METHODS: We screened for mutations in ENDOGLIN(ENG), SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6 and SMAD8 genes, which are involved in the TGF-beta/BMP signallings, in 23 patients with IPAH who had no mutations in BMPR2 or ALK1. RESULTS: A nonsense mutation in SMAD8 designated c.606 C>A, p.C202X was identified in one patient. The father of this patient was also identified as having the same mutation. Functional analysis showed the truncated form of the SMAD8 C202X protein was not phosphorylated by constitutively active ALK3 and ALK1. The SMAD8 mutant was also unable to interact with SMAD4. The response to BMP was analysed using promoter-reporter activities with SMAD4 and/or ca-ALK3. The transcriptional activation of the SMAD8 mutant was inefficient compared with the SMAD8 wild type. CONCLUSION: We describe the first mutation in SMAD8 in a patient with IPAH. Our findings suggest the involvement of SMAD8 in the pathogenesis of PAH.

BACKGROUND: In Japan, routine clinical care does not normally involve the use of a monitoring device to guide the administration of neuromuscular blocking drugs or their antagonists. Although most previous reports demonstrate that sugammadex offers more rapid and reliable antagonism from rocuronium-induced neuromuscular blockade, this advantage has not been confirmed in clinical settings when no neuromuscular monitoring is used. In this multicenter observational study, we sought to determine whether sugammadex reduces the incidence of postoperative residual weakness compared with neostigmine when the administration of rocuronium and its antagonists is not guided by neuromuscular monitoring. METHODS: This study was conducted in two 5-month periods that preceded and followed the introduction of sugammadex into clinical practice in Japan. Five university-affiliated teaching hospitals participated in this study. Neostigmine was used to antagonize rocuronium-induced neuromuscular blockade in the first phase, and sugammadex was used in the second phase. The timing and doses of rocuronium, neostigmine, and sugammadex were determined by the attending anesthesiologists without the use of neuromuscular function monitoring devices. To ascertain the incidence of postoperative residual neuromuscular weakness, the train-of-four ratio (TOFR) was determined acceleromyographically after tracheal extubation. Since our practice also does not usually involve calibration and normalization of accelerographic responses, both TOFR <0.9 and TOFR <1.0 were used as the criteria for defining postoperative residual weakness. RESULTS: In the first phase, 109 patients received neostigmine (average dose 33 µg/kg) and 23 patients were considered (by clinical criteria) to have adequate recovery and did not receive neostigmine (spontaneous recovery group). In the second phase, 117 patients received sugammadex (average dose 2.7 mg/kg) for antagonism of rocuronium-induced blockade. The incidence (95% confidence interval) of TOFR <0.9 under spontaneous recovery, after neostigmine, and after sugammadex, was 13.0% (2.8%-33.6%), 23.9% (16.2%-33.0%), and 4.3% (1.7%-9.4%), respectively. The incidence (95% confidence interval) of TOFR <1.0 in these groups was 69.6% (47.1%-86.6%), 67.0% (57.3%-75.7%), and 46.2% (36.9%-55.6%), respectively. The use of sevoflurane in the neostigmine group and the short interval between the administration of the last doses of rocuronium and sugammadex were associated with a higher incidence of postoperative residual weakness. CONCLUSIONS: This study demonstrated that the risk of TOFR <0.9 after tracheal extubation after sugammadex remains as high as 9.4% in a clinical setting in which neuromuscular monitoring (objective or subjective) was not used. Our finding underscores the importance of neuromuscular monitoring even when sugammadex is used for antagonism of rocuronium-induced neuromuscular block.

We evaluated the efficacy of bacteriophage (phage) therapy by using a murine model of gut-derived sepsis caused by Pseudomonas aeruginosa that closely resembles the clinical pathophysiology of septicemia in humans. Oral administration of a newly isolated lytic phage strain (KPP10) significantly protected mice against mortality (survival rates, 66.7% for the phage-treated group versus 0% for the saline-treated control group; P<0.01). Mice treated with phage also had lower numbers of viable P. aeruginosa cells in their blood, liver, and spleen. The levels of inflammatory cytokines (tumor necrosis factor alpha TNF-alpha, interleukin-1beta [IL-1beta], and IL-6) in blood and liver were significantly lower in phage-treated mice than in phage-untreated mice. The number of viable P. aeruginosa cells in fecal matter in the gastrointestinal tract was significantly lower in phage-treated mice than in the saline-treated control mice. We also studied the efficacy of phage treatment for intraperitoneal infection caused by P. aeruginosa and found that phage treatment significantly improved the survival of mice, but only under limited experimental conditions. In conclusion, our findings suggest that oral administration of phage may be effective against gut-derived sepsis caused by P. aeruginosa.

The main bone age assessment methods are the Greulich-Pyle and Tanner-Whitehouse 2 methods, both of which involve left hand and wrist radiographs. Several other bone age assessment methods have been developed, including ultrasonographic, computerized, and magnetic resonance (MR) imaging methods. The ultrasonographic method appears unreliable in children with delayed and advanced bone age. MR imaging is noninvasive; however, bone age assessment using MR imaging is relatively new, and further examinations are needed. An automated method for determining bone age, named BoneXpert, has been validated for Caucasian children with growth disorders and children of various ethnic groups. Sex hormones are necessary for bone growth and maturation in children with a bone age corresponding to normal pubertal age, and estrogen is essential for growth plate closure. Bone age is an effective indicator for diagnosing and treating various diseases. A new method for adult height prediction based on bone age has been developed using BoneXpert, in addition to the commonly used Bayley-Pinneau and Tanner-Whitehouse mark II methods. Furthermore, bone age may become a predictor for the timing of peak height velocity and menarche.

INTRODUCTION: To test the hypothesis that the administration of antithrombin concentrate improves disseminated intravascular coagulation (DIC), resulting in recovery from DIC and better outcomes in patients with sepsis, we conducted a prospective, randomized controlled multicenter trial at 13 critical care centers in tertiary care hospitals. METHODS: We enrolled 60 DIC patients with sepsis and antithrombin levels of 50 to 80% in this study. The participating patients were randomly assigned to an antithrombin arm receiving antithrombin at a dose of 30 IU/kg per day for three days or a control arm treated with no intervention. The primary efficacy end point was recovery from DIC on day 3. The analysis was conducted with an intention-to-treat approach. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) scoring system. The systemic inflammatory response syndrome (SIRS) score, platelet count and global markers of coagulation and fibrinolysis were measured on day 0 and day 3. RESULTS: Antithrombin treatment resulted in significantly decreased DIC scores and better recovery rates from DIC compared with those observed in the control group on day 3. The incidence of minor bleeding complications did not increase, and no major bleeding related to antithrombin treatment was observed. The platelet count significantly increased; however, antithrombin did not influence the sequential organ failure assessment (SOFA) score or markers of coagulation and fibrinolysis on day 3. CONCLUSIONS: Moderate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000882.

OBJECTIVE: Previous studies have reported distinct serological profiles of lipid, urate and ferritin in Western patients with amyotrophic lateral sclerosis (ALS). We aimed to examine the levels of these serological factors and their relationship to disease progression in Japanese ALS patients. METHODS: Ninety-two patients with definite or probable ALS who fulfilled the revised El Escorial criteria were analyzed for clinical and serological variables. Serological data at the time diagnosed with ALS were compared to those of 92 age/sex/body mass index-matched healthy controls. RESULTS: Compared to controls, urate and creatinine (Cr) levels were decreased and ferritin levels were increased significantly in sera of male and female patients with ALS. Significant increases of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were found in female ALS patients. The annual decline of ALS Functional Rating Scale-Revised (ALS-FRS) and forced vital capacity (FVC) were inversely correlated with serum TC, LDL-C, Cr and urate levels, and were positively correlated with serum ferritin levels. Multivariate analysis showed that the rapid worsening of annual ALS-FRS and FVC was associated with serum levels of TC, LDL-C, Cr, urate and ferritin. CONCLUSION: The present study indicated that serum levels of TC, LDL-C, Cr, urate and ferritin were correlated with clinical deterioration in ALS patients. These results are similar to those in Western patients. Metabolic and nutritional conditions of lipid, urate and iron could contribute to disease progression in ALS patients. Further studies investigating high nutrition diets and iron chelation for the treatment of ALS are warranted.

Congenital heart defects (CHD) are very common in patients with trisomy 18 (T18) and trisomy 13 (T13). The surgical indication of CHD remains controversial since the natural history of these trisomies is documented to be poor. To investigate the outcome of CHD in patients with T18 and T13, we collected and evaluated clinical data from 134 patients with T18 and 27 patients with T13 through nationwide network of Japanese Society of Pediatric Cardiology and Cardiac Surgery. In patients with T18, 23 (17%) of 134 were alive at this survey. One hundred twenty-six (94%) of 134 patients had CHDs. The most common CHD was ventricular septal defect (VSD, 59%). Sixty-five (52%) of 126 patients with CHD developed pulmonary hypertension (PH). Thirty-two (25%) of 126 patients with CHD underwent cardiac surgery and 18 patients (56%) have survived beyond postoperative period. While palliative surgery was performed in most patients, six cases (19%) underwent intracardiac repair for VSD. Operated patients survived longer than those who did not have surgery (P < 0.01). In patients with T13, 5 (19%) of 27 patients were alive during study period. Twenty-three (85%) of 27 patients had CHD and 13 (57%) of 27 patients had PH. Atrial septal defect was the most common form of CHD (22%). Cardiac surgery was done in 6 (26%) of 23 patients. In this study, approximately a quarter of patients underwent surgery for CHD in both trisomies. Cardiac surgery may improve survival in selected patients with T18.

Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs.

OBJECTIVE: Pulmonary tumor thrombotic microangiopathy (PTTM) is a unique, rare and fatal form of pulmonary arterial tumor embolism. The aim of this study was to evaluate the clinical characteristics and pathological and immunohistochemical findings of PTTM. METHODS: Autopsy records dated between January 1983 and May 2008 in our hospital were reviewed, and those of patients who died from pulmonary tumor embolism resulting from malignant neoplasm were retrieved. The relevant tissue slides were reevaluated and examined immunohistochemically to confirm the diagnosis. RESULTS: Among 2,215 consecutive autopsy cases of carcinoma, 30 patients (1.4%) were diagnosed with definitive PTTM. The common symptom was progressive dyspnea. A hypercoagulative state was observed in all measured cases (n = 21). The chest computed tomography findings (n = 6) included consolidation, ground-glass opacity, small nodules and a tree-in-bud appearance. Perfusion scans were performed in seven patients, six of whom demonstrated multiple small defects. The median survival time after the initiation of oxygen supplementation was nine days. The most frequent primary site was the stomach (n = 18 ; 60%) , and the most frequent histological type was adenocarcinoma (28/30 ; 93.3%) . The immunohistochemical findings for tumor cells located within the tumor emboli were positive for vascular endothelial growth factor (28/29 ; 96.6%) and tissue factor (29/29 ; 100%). CONCLUSION: Clinicians should suspect PTTM in cancer patients who exhibit acute worsening respiratory insufficiency accompanied by a hypercoagulative state without embolism in major pulmonary arteries. The PTTM patients evaluated in our study had very poor prognoses. Vascular endothelial growth factor and tissue factor may play important roles in PTTM.

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.

Importance: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). Objective: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. Design, Setting, and Participants: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. Main Outcomes and Measures: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. Results: Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE. Conclusions and Relevance: Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a fatal disorder for which there are currently no specific or effective medical treatments. A multicentre, prospective, randomized, controlled clinical trial was conducted to assess the efficacy of inhaled N-acetylcysteine (NAC) monotherapy in Japanese patients with early stage IPF. METHODS: Eligible patients had well-defined IPF of mild-to-moderate severity, with no desaturation on exercise. Of 100 patients screened, 76 were randomly assigned to an NAC treatment group (group A; n = 38) that received 352.4 mg of NAC by inhalation twice daily or to a control group (group B; n = 38) that received no therapy. The primary endpoint was the change from baseline in forced vital capacity (FVC) at 48 weeks. RESULTS: There were no significant overall differences in the change in FVC between groups A and B. Post hoc exploratory analyses showed that NAC therapy was associated with stability of FVC in (i) a subset of patients with initial FVC <95% of predicted (n = 49; difference in FVC decline 0.12 L; P = 0.02) and (ii) in patients with initial diffusing capacity of carbon monoxide <55% of predicted (n = 21; difference in FVC decline 0.17 L; P = 0.009). CONCLUSIONS: These findings indicate that NAC monotherapy may have some beneficial effect in patients with early stage IPF. Further trials in more select IPF populations with progressive disease are required to prove the efficacy of inhaled NAC.