Early-Onset Chronic Inflammatory Disease Associated with Maternal Microchimerism

Maternal microchimerism (mMc) refers to the presence of a small population of cells originating from the mother. Whether mMc leads to autoimmune responses in children remains controversial. We describe here an 11-year-old boy with persistent fever and elevated levels of C-reactive protein from infancy onward. During infancy, the patient presented with high fever, skin rashes, and hepatic dysfunction. Careful examination including a liver biopsy failed to reveal the cause. At 4 years old, petechiae developed associated with thrombocytopenia and positive anti-dsDNA autoantibodies. Steroid pulse therapy was effective, but the effect of low-dose prednisone was insufficient. At age 9, an extensive differential diagnosis was considered especially for infantile onset autoinflammatory disorders but failed to make a definitive diagnosis. On admission, the patient exhibited short stature, hepatosplenomegaly, generalized superficial lymphadenopathy, and rashes. Laboratory findings revealed anemia, elevated levels of inflammation markers, and hypergammaglobulinemia. Serum complement levels were normal. Serum levels of IL-6 and B-cell activating factor were elevated. Viral infections were not identified. Although HLA typing revealed no noninherited maternal antigens in lymphocytes, female cells were demonstrated in the patient’s skin and lymph nodes, suggesting that maternal microchimerism might be involved in the pathogenesis of fever without source in infants

A Retrospective Analysis of Transfusion Management for Obstetric Hemorrhage in a Japanese Obstetric Center

Background. Since cryoprecipitate, fibrinogen concentrate, or recombinant activated factor VII is not approved by public medical insurance in Japan, we retrospectively assessed blood product usage in patients with obstetric hemorrhage at our tertiary obstetric center. Material and Methods. 220 patients with obstetric hemorrhagic disorders who underwent blood product transfusion in our institution during a 5-year period were reviewed for the types and volumes of blood products transfused. Results. There was a significant positive correlation (P< 0.001) between the volume of RCC (red blood cell concentrate) transfused and that of FFP (fresh frozen plasma), irrespective of underlying obstetric disorders. The median of FFP to RCC ratio in each patient was 1.3–1.4, when 6 or more units of RCC were transfused. Conclusions. In transfusion for massive obstetric hemorrhage in terms of appropriate supplementation of coagulation factors, the transfusion of RCC : FFP = 1 : 1.3–1.4 may be desirable

Repression of factor VIII inhibitor development with apoptotic factor VIII-expressing embryonic stem cells

Development of factor VIII (fVIII)-neutralizing antibodies, called inhibitors, is a challenging problem in the management of hemophilia A patients. We explored the possibility of pretreatment with apoptotic fVIII-expressing embryonic stem (ES) cells to prevent the development of fVIII inhibitors. Murine ES cells integrated with the human F8 gene were differentiated into embryoid bodies, dissociated to a single cell suspension, subjected to hypo-osmotic shock to induce apoptosis, and intraperitoneally injected into hemophilia A mice. Inhibitors were induced by periodic intraperitoneal injections of recombinant human fVIII (rhfVIII). In the groups in which intraperitoneal injections of rhfVIII began at 1-3 weeks after pretreatment, the titers of inhibitors were significantly lower after the third administration of rhfVIII compared with that in the control group in which apoptotic Ainv18 ES cells (without the human F8 gene) were used for pretreatment, and continued to show lower levels until the sixth administration of rhfVIII. These results suggest that pretreatment with apoptotic hfVIII-expressing ES cells might be promising for the prevention of fVIII inhibitor development in hemophilia A patients

Destruxin E Decreases Beta-Amyloid Generation by Reducing Colocalization of Beta-Amyloid-Cleaving Enzyme 1 and Beta-Amyloid Protein Precursor

Alzheimer-disease-associated beta-amyloid (A beta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (beta APP): the extracellular portion is shed by cleavage in the juxtamembrane region by beta-amyloid-cleaving enzyme (BACE)/beta-secretase, after which it is cleaved by presenilin (PS)/gamma-secretase near the middle of the transmembrane domain. Thus, inhibition of either of the secretases reduces A beta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce A beta production without inhibition of the secretases. Such compounds are expected to avoid some of the side effects of secretase inhibitors. Here, we report that destruxin E (Dx-E), a natural cyclic hexadepsipeptide, reduces A beta generation without affecting BACE or PS/gamma-secretase activity. In agreement with this, Dx-E did not inhibit Notch signaling. We found that Dx-E decreases colocalization of BACE1 and beta APP, which reduces beta-cleavage of beta APP. Therefore, the data demonstrate that Dx-E represents a novel A beta-reducing process which could have fewer side effects than secretase inhibitors. Copyright (C) 2009 S. Karger AG, Base

高齢の非代償性心不全患者において、非心血管疾患、特に感染症は重要な死因である

BACKGROUND:Despite marked improvements in treatment strategies for heart failure (HF), the mortality rate of elderly patients with HF is still high. Detailed causes of death have not been fully understood.METHODS AND RESULTS:We studied 459 consecutive patients with acute decompensated HF (ADHF) emergently admitted to our hospital from 2007 to 2011. Patients were divided into 2 groups: <75 years old (younger group; n = 225) and ≥75 years old (elderly group; n = 234). All-cause death, cardiovascular death, and noncardiovascular death were assessed as adverse outcomes. Compared with the younger group, the elderly group was characterized by a higher proportion of women and hypertensive patients and higher left ventricular ejection fraction. During a mean follow-up of 20.7 months, a total of 174 patients (37.9%) died. All-cause death was significantly higher in the elderly group than in the younger group (46.6% vs 28.9%; P < .0001), and this difference was caused by an increase in noncardiovascular deaths (20.9% vs 9.3%; P < .001), especially deaths due to infection (10.7% vs 4.0%; P < .01). Cardiovascular deaths did not differ between the 2 groups.CONCLUSIONS:Noncardiovascular deaths, most of which were caused by infection, were frequent among elderly patients with ADHF.博士（医学）・甲第629号・平成27年3月16日Copyright © 2014 Elsevier Inc. All rights reserved

Cholecalciferol Supplementation Attenuates Bone Loss in Incident Kidney Transplant Recipients: A Prespecified Secondary Endpoint Analysis of a Randomized Controlled Trial

Vitamin D deficiency, persistent hyperparathyroidism, and bone loss are common after kidney transplantation (KTx). However, limited evidence exists regarding the effects of cholecalciferol supplementation on parathyroid hormone (PTH) and bone loss after KTx. In this prespecified secondary endpoint analysis of a randomized controlled trial, we evaluated changes in PTH, bone metabolic markers, and bone mineral density (BMD). At 1 month post-transplant, we randomized 193 patients to an 11-month intervention with cholecalciferol (4000 IU/d) or placebo. The median baseline 25-hydroxyvitamin D (25[OH]D) level was 10 ng/mL and 44% of participants had osteopenia or osteoporosis. At the end of the study, the median 25(OH)D level was increased to 40 ng/mL in the cholecalciferol group and substantially unchanged in the placebo group. Compared with placebo, cholecalciferol significantly reduced whole PTH concentrations (between-group difference of −15%; 95% confidence interval [CI] −25 to −3), with greater treatment effects in subgroups with lower 25(OH)D, lower serum calcium, or higher estimated glomerular filtration rate (pint < 0.05). The percent change in lumbar spine (LS) BMD from before KTx to 12 months post-transplant was −0.2% (95% CI −1.4 to 0.9) in the cholecalciferol group and −1.9% (95% CI −3.0 to −0.8) in the placebo group, with a significant between-group difference (1.7%; 95% CI 0.1 to 3.3). The beneficial effect of cholecalciferol on LS BMD was prominent in patients with low bone mass pint < 0.05). Changes in serum calcium, phosphate, bone metabolic markers, and BMD at the distal radius were not different between groups. In mediation analyses, change in whole PTH levels explained 39% of treatment effects on BMD change. In conclusion, 4000 IU/d cholecalciferol significantly reduced PTH levels and attenuated LS BMD loss after KTx. This regimen has the potential to eliminate vitamin D deficiency and provides beneficial effects on bone health even under glucocorticoid treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Tsujita M., Doi Y., Obi Y., et al. Cholecalciferol Supplementation Attenuates Bone Loss in Incident Kidney Transplant Recipients: A Prespecified Secondary Endpoint Analysis of a Randomized Controlled Trial. Journal of Bone and Mineral Research 37, 303 (2022); https://doi.org/10.1002/jbmr.4469

胎盤増殖因子の可溶性Fms様チロシンキナーゼ-1に対する血中濃度比の上昇は安定冠動脈疾患患者における有害事象発症の予測因子である

OBJECTIVE: To investigate the predictive values of placental growth factor (PlGF) and its endogenous antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1), for the long-term prognosis of patients with stable coronary artery disease (CAD). Both PlGF and sFlt-1 play important roles in the pathological mechanisms of atherosclerosis. We recently demonstrated that the plasma levels of these molecules are correlated with the severity of coronary atherosclerosis. METHODS: We enrolled 464 patients with stable CAD who consecutively underwent coronary angiography. Baseline blood samples were collected from the femoral artery immediately before coronary angiography (after the administration of 20 units of heparin), and the plasma levels of PlGF and sFlt-1 were measured. A Cox proportional hazard regression analysis was performed to evaluate the relationship between these parameters and the occurrence of all-cause death (ACD) and total cardiovascular events (TCVE) during a median follow-up of 3.3 years. RESULTS: A total of 31 ACDs and 51 TCVEs occurred. Patients with higher PlGF/sFlt-1 ratios (>4.22×10(-2)) had a significantly higher risk of both ACD and TCVE than patients with lower ratios (<4.22×10(-2)) (hazard ratio [HR]: 3.32, 95% confidence interval [CI]: 1.43 to 7.72, p=0.005, and HR: 2.23, 95% CI: 1.23 to 4.03, p=0.008, respectively). A multivariate analysis showed the PlGF/sFlt-1 ratio to be an independent predictor for ACD, but not TCVE.博士（医学）・甲615号・平成26年3月17日発行元の規定により、本文の登録不可。本文は以下のURLを参照 "http://dx.doi.org/10.2169/internalmedicine.52.9073

可溶性Flt-1産生低下は、心筋リモデリングおよび心不全増悪に寄与する

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti–placental growth factor–neutralizing antibody prevented pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.博士（医学）・乙第1384号・平成28年11月24日© 2016 American Heart Association, Inc.The definitive version is available at " https://doi.org/10.1161/HYPERTENSIONAHA.116.07371