Effectiveness of continuous allergenic food intake for acute food protein-induced enterocolitis syndrome.

Continuous intake of allergenic food is a safe and efficient treatment strategy for patients with a prolonged course of acute food protein-induced enterocolitis syndrome. The initial dose, dose escalation rate, and starting age for continuous allergenic food intake need further clarification.

Optimal tentative abdominal closure for open abdomen: a multicenter retrospective observational study (OPTITAC study).

BACKGROUND: Primary fascia closure is often difficult following an open abdomen (OA). While negative-pressure wound therapy (NPWT) is recommended to enhance successful primary fascia closure, the optimal methods and degree of negative pressure remain unclear. This study aimed to elucidate optimal methods of NPWT as a tentative abdominal closure for OA to achieve primary abdominal fascia closure. MATERIALS AND METHODS: A multicenter, retrospective, cohort study of adults who survived OA greater than 48 h was conducted in 12 institutions between 2010 and 2022. The achievement of primary fascia closure and incidence of enteroatmospheric fistula were examined based on methods (homemade, superficial NPWT kit, or open-abdomen kit) or degrees of negative pressure (<50, 50-100, or >100 mmHg). A generalized estimating equation was used to adjust for age, BMI, comorbidities, etiology for laparotomy requiring OA, vital signs, transfusion, severity of critical illness, and institutional characteristics. RESULTS: Of the 279 included patients, 252 achieved primary fascia closure. A higher degree of negative pressure (>100 mmHg) was associated with fewer primary fascia closures than less than 50 mmHg [OR, 0.18 (95% CI: 0.50-0.69), P =0.012] and with more frequent enteroatmospheric fistula [OR, 13.83 (95% CI: 2.30-82.93)]. The methods of NPWT were not associated with successful primary fascia closure. However, the use of the open-abdomen kit was related to a lower incidence of enteroatmospheric fistula [OR, 0.02 (95% CI: 0.00-0.50)]. CONCLUSION: High negative pressure (>100 mmHg) should be avoided in NPWT during tentative abdominal closure for OA.

Benefits and Risks of Delayed Surgery for Ventricular Septal Rupture after Acute Myocardial Infarction.

The timing of surgery for ventricular septal rupture (VSR) after acute myocardial infarction (AMI) remains controversial. This study investigated the benefits and risks of delayed surgery for post-AMI VSR and examined differences in echocardiographic findings between early and delay groups.A total of 38 consecutive patients with post-AMI VSR who underwent surgery at our hospital between May 2003 and November 2020 were retrospectively analyzed. Our strategy was to delay surgery until 2 weeks after AMI. If patients demonstrated organ dysfunction, we considered early surgery. Patients were divided into early (n = 20; 53%) and delay (n = 18; 47%) groups. Risks and benefits were investigated based on echocardiographic findings during the waiting period. The delay group had more preoperative intravenous catheter infections (P = 0.008) but fewer reoperations (P = 0.02) and lower operative mortality (P = 0.04) than the early group. The VSR defect diameter and total pulmonary blood flow to total systemic blood flow (Qp/Qs) increased in both groups while waiting. Nevertheless, the early group had a significantly higher Qp/Qs change rate than the delay group (P = 0.05). The 30 day and hospital mortality rates were 5.3% and 13.2%, respectively.The VSR defect diameter and Qp/Qs in both groups increased with time and can therefore become risk factors. Nonetheless, the benefit of waiting exceeded the risk because our outcomes were better than those previously reported.

Oropharyngeal symptoms without systemic reactions as a risk factor for food allergen intolerance: a longitudinal pediatric study.

BACKGROUND: The determinants of tolerance to food allergens are not fully understood. We aimed to elucidate the longitudinal association between oropharyngeal symptoms without systemic reactions (OSw/oS) and tolerance to food allergens. METHODS: We included all patients diagnosed with single food allergy to egg (n = 121), milk (n = 55), and wheat (n = 41) using the oral food challenge test (OFC) from 2014 to 2017. These patients received oral immunotherapy at home and/or in the hospital after diagnosis by OFC. We compared the incidence proportion of tolerance within 2 years by OSw/oS and other variables for 217 patients with food allergy. We defined OSw/oS as isolated symptoms of oropharyngeal discomfort that occurred after ingestion of a safe dose of the allergenic food determined by the OFC in the first 6 months. RESULTS: Of the 217 patients (median age 37.5 months, male 64.5%), 53 developed OSw/oS (24.4%), and 151 (egg, 85 milk, 36 and wheat, 30) attained tolerance in 2 years. Patients without OSw/oS showed a significantly higher incidence of tolerance than those with the symptoms (crude hazard ratio [HR] 5.62, 95% confidence interval [CI] 3.58-8.82, p < 0.001). The association was consistently significant in the multivariable model (adjusted HR 9.50, 95% CI 5.25-17.20, p < 0.001) independent of other risk factors for intolerance, such as concomitant bronchial asthma (adjusted HR 3.33), history of anaphylaxis (adjusted HR 2.16), milk allergy (adjusted HR 2.02), and allergic symptoms with low dose OFC (adjusted HR 1.52). CONCLUSION: Our results suggest that OSw/oS may be a risk factor for intolerance to food allergens. To reveal a high risk of food allergen intolerance may help patients and their families as well as healthcare professionals prepare for the challenge of continuing oral immunotherapy.

Transient hyperphosphatasemia: Possible association with pediatric acute respiratory infection.

IMPORTANCE: Acute respiratory infections are quite prevalent in children. Transient hyperphosphatasemia (TH) is defined as the transient elevation of serum alkaline phosphatase (ALP) level, which occurs mainly in infants and children without liver or bone disorders. Although no apparent cause has been identified, a possible association of respiratory infections with TH has been reported in the literature. OBJECTIVE: In this study, we aimed to investigate the association between TH and respiratory infectious diseases. METHODS: We collected the results of biochemical investigations, including ALP level, for a period of 5 years in our hospital. We then examined the patients with transiently elevated ALP levels of > 2000 U/L. RESULTS: During the observation period, 1501 blood samples were collected from 1097 patients. Marked elevation of serum ALP level was observed in 12 patients. All patients with hyperphosphatasemia, except for one with Fanconi syndrome attributable to the underlying Wilson's disease, were aged < 5 years and were diagnosed with TH. Ten of these 11 patients with TH had acute respiratory infections. Marked ALP elevation was not found in any patients with non-inflammatory diseases. ALP isoenzyme profiles showed a characteristic pattern in all six patients in whom the ALP isoenzyme test was conducted. INTERPRETATION: Our results suggest an association between respiratory infections and TH. The consideration of TH in patients with acute respiratory infections may lead to earlier and accurate diagnosis of this condition, thereby avoiding unnecessary medical interventions.

Development of Acquired Factor V Inhibitor After Surgical Procedure Without the Use of Fibrin Tissue Adhesives: A Case Report.

Development of acquired factor V (FV) inhibitor is a rare coagulation disorder. Production of heteroantibodies against bovine FV, a contaminant in fibrin tissue adhesives, is a common cause of this condition in the field of surgery. The development of recombinant thrombin eliminated contamination of bovine FV, and infrequent use of bovine thrombin has decreased the risk of FV inhibitor development. Here, we report the case of a 43-year-old man who had marked prolongation of prothrombin time and activated partial thromboplastin time after surgery. Mixing coagulation studies with normal plasma and patient's plasma suggested the presence of an inhibitor. Clotting factor assays revealed that FV activity decreased to <1% with positive FV inhibitor titer (9.2 Bethesda units). The diagnosis of the FV inhibitor was confirmed. Overt bleeding was not observed during the course of hospitalization. His coagulation abnormalities rapidly normalized without any medical intervention. A careful review of his medical records revealed that no tissue adhesives were used in the patient, and the FV inhibitor would likely be autoantibodies. Antibiotic use during the perioperative period or the surgical procedure itself may trigger the occurrence of FV inhibitors. This case highlights that FV inhibitor may develop after the surgical procedure even without a history of the use of fibrin tissue adhesives. Surgeons and hematologists should be aware that this rare but potentially life-threatening condition may occur after the surgical procedure.

Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

[Acute Necrotizing Esophagitis Occurred after Lung Resection for Lung Cancer].

The patient was a 78-year-old man who had undergone left lung segmentectomy (S6) with lymph node dissection for lung adenocarcinoma. One year and 5 months later, lung partial resection was performed for the lung cancer recurrence and the hematemesis was noted on the next day of surgery. Upper gastrointestinal endoscopy revealed extensive black necrosis on the mucosa of the esophagus, which was diagnosed as acute necrotizing esophagitis. To treat the bleeding, the exposed esophageal vessels were clipped via endoscopy several times. The endoscopy on the 64th post-operative day showed the mucosa recovered and he could be discharged on the 85th day. The exact etiology of acute necrotizing esophagitis is unknown in most cases.

Enhancement of Tissue Factor Expression in Monocyte-Derived Dendritic Cells by Pentraxin 3 and Its Modulation by C1 Esterase Inhibitor.

BACKGROUND: We have previously shown that human monocyte-derived dendritic cells (moDCs) may participate in immune system-mediated hypercoagulable state through enhanced tissue factor (TF) expression and that the complement system may be involved in this process. OBJECTIVES: The aim of this study was to explore the role of pentraxin 3 (PTX3) and the complement system in enhanced TF expression in moDCs. METHODS: moDCs were generated from isolated human monocytes. PTX3 levels in whole human blood supplemented with moDCs were determined after lipopolysaccharide (LPS) stimulation. PTX3 release by the generated moDCs upon LPS stimulation was also assessed. The effect of PTX3 on whole blood coagulation was investigated using thromboelastometric analysis. TF expression in stationary moDCs treated with LPS and/or PTX3 was determined by measuring TF activity. The effect of complement inhibitors on TF activity in moDCs treated with LPS and/or PTX3 under low-shear conditions was evaluated. RESULTS: PTX3 levels were higher in whole blood supplemented with moDCs than in the presence of monocytes and were further elevated by LPS stimulation. PTX3 release from generated moDCs was also increased by LPS stimulation. PTX3 reduced whole blood coagulation time in a dose-dependent manner. However, PTX3 did not increase TF expression in stationary moDCs. Under low-shear conditions, PTX3 increased TF expression in moDCs. C1 esterase inhibitor (C1-inh) suppressed this effect. CONCLUSIONS: PTX3 might have a thrombophilic activity and enhance TF expression in moDCs under low-shear conditions. Furthermore, suppression of moDC-associated hypercoagulability by C1-inh might be partly ascribed to its inhibitory effect on PTX3.

Persistent Idiopathic Facial Pain Associated with Somatoform Disorder in an 11-Year-Old Boy.

Persistent idiopathic facial pain (PIFP) is a poorly understood chronic disorder that rarely occurs in children. An 11-year-old boy initially presented with right cheek pain and a streptococcal infection 6 weeks previously. Facial cellulitis was suspected, which was resolved by antibiotic treatment. The right cheek pain recurred within 4 weeks of this initial visit. Because the antibiotic treatment did not relieve the pain, the patient visited our outpatient clinic. Physical examination revealed facial tenderness in an area that corresponded with the region supplied by the second branch of the trigeminal nerve (maxillary nerve), suggesting trigeminal neuralgia (TN). However, brain magnetic resonance imaging revealed no vascular compression. Furthermore, the continuous nagging and dull nature of the pain experienced by the patient differed from the sudden and severe nature of pain associated with TN. Subsequently, PIFP was diagnosed. The patient was unable to attend school because of prolonged lassitude, nausea, headache, and anorexia. Psychological counseling revealed psychological stress related to his out-of-school life. Upon learning stress management through psychotherapy, his general malaise gradually improved, and he was able to attend school with more facial expressions. This case indicates the psychogenic aspect of PIFP as well as the value of psychological counseling.

Experimental hypercoagulable state induced by tissue factor expression in monocyte-derived dendritic cells and its modulation by C1 inhibitor.

The crosstalk between immune and coagulation systems plays pivotal roles in host defense, which may involve monocyte-derived dendritic cells (moDCs). Our objectives were to elucidate the role of moDCs in coagulation under inflammatory conditions and the involvement of the complement system. We assessed the effects of lipopolysaccharide (LPS)-stimulated moDCs on coagulation using whole blood thromboelastometry in the presence of complement inhibitors. The sum of clotting time and clot formation time (CT plus CFT) in whole blood thromboelastometry was significantly more reduced in the presence of moDCs than in the absence of monocytes or moDCs and in the presence of monocytes, indicating a more potent coagulability of moDCs. The mRNA expression of coagulation-related proteins in moDCs was analyzed by quantitative PCR, which showed an increase only in the mRNA levels of tissue factor (TF). TF protein expression was assessed by western blot analysis and an activity assay, revealing higher TF expression in moDCs than that in monocytes. The in vitro moDC-associated hypercoagulable state was suppressed by a TF-neutralizing antibody, whereas LPS enhanced the in vitro hypercoagulation further. C1 inhibitor suppressed the in vitro LPS-enhanced whole blood hypercoagulability in the presence of moDCs and the increased TF expression in moDCs. These results suggest a significant role of moDCs and the complement system through TF expression in a hypercoagulable state under inflammatory conditions and demonstrate the suppressive effects of C1 inhibitor on moDC-associated hypercoagulation.

Acute ethanol intoxication suppresses pentraxin 3 expression in a mouse sepsis model involving cecal ligation and puncture.

Acute ethanol intoxication impairs immunological reactions and increases the risk of sepsis; however, the underlying mechanism remains unclear. Pentraxin (PTX) 3 is a humoral pattern recognition receptor whose levels rapidly increase in response to inflammation. PTX3 production is triggered by tumor necrosis factor (TNF)-α and is mediated by c-Jun N-terminal kinase (JNK). As PTX3 exerts protective effects against sepsis as well as acute lung injury, we investigated whether acute ethanol exposure exacerbates sepsis by altering PTX3 expression. Sepsis was induced in C57/BL6 mice by cecal ligation and puncture (CLP) after ethanol/saline administration. Survival rates were significantly lower in ethanol-treated than in saline-treated mice. Increased vascular permeability and attenuation of PTX3 expression were observed in the lungs of ethanol-treated mice 4 h after CLP. Concomitant with a delayed increase of plasma TNF-α in ethanol-treated mice, plasma PTX3 was also suppressed in the early phase of sepsis. Although TNF-α level in ethanol-treated mice exceeded that in saline-treated mice 16 h after CLP, PTX3 levels were still suppressed in the former group. JNK phosphorylation in lung tissue was suppressed in both groups 4 and 16 h after CLP. Furthermore, JNK phosphorylation in ethanol-treated human umbilical vein endothelial cells was suppressed even in the presence of exogenous TNF-α, resulting in inhibition of PTX3 mRNA and protein expression. Our results suggest that ethanol suppresses de novo PTX3 synthesis via two mechanisms - i.e., suppression of TNF-α production and inhibition of JNK phosphorylation. PTX3 suppression may therefore contribute to exacerbation of sepsis in acute ethanol intoxication.

Juvenile polymyositis associated with anti-OJ (anti-isoleucyl-tRNA synthetase) autoantibody in a 13-year-old girl.

A 13-year-old girl was admitted for persistent thigh pain and remittent fever and was diagnosed as having juvenile polymyositis. Although the initial treatment with 2 cycles of methylprednisolone pulse therapy failed to achieve full remission, the second-line treatment with intravenous cyclophosphamide pulse therapy was effective. Anti-OJ antibody, which is one of anti-aminoacyl-tRNA synthetase (ARS) antibodies and is rare in adult polymyositis, was detected. Assessment of anti-ARS autoantibodies may facilitate diagnosis and management of juvenile polymyositis.

Therapeutic approaches for treating hemophilia A using embryonic stem cells.

Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future.

Persistent endothelial damage after intravenous immunoglobulin therapy in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. Although endothelial cell damage associated with vasculitis might lead to the hypercoagulability that is involved in coronary artery disease, the changes in coagulation after intravenous immunoglobulin therapy (IVIG) have not been well investigated in KD. The aims of this study were to address the changes in coagulation before and after IVIG in KD, and to further elucidate the coagulation-inflammation axis, with special attention to endothelial damage. METHODS: We retrospectively collected the laboratory data before and after IVIG in 26 pediatric KD patients treated at the Nara Prefecture Western Medical Center between May 2010 and April 2012. Prothrombin time (PT), activated partial thromboplastin time (APTT) and levels of fibrin/fibrinogen degradation products (FDP) and D-dimer were assessed as coagulation markers. Fibrinogen, ferritin, serum amyloid A, procalcitonin and urine ß2 microglobulin were assessed as inflammation markers. Thrombomodulin, antithrombin, factor VIII activity (FVIII:C), and von Willebrand factor antigen (VWF:Ag) were used to assess endothelial damage. RESULTS: Prolonged PT and APTT before IVIG were significantly shortened after IVIG, and elevated levels of FDP and D-dimer were significantly decreased. Elevated levels of inflammation markers had decreased significantly after IVIG, but levels of FVIII:C and VWF:Ag remained high, even after IVIG. CONCLUSIONS: Ameliorated inflammation by IVIG might improve the hypercoagulable state. Nevertheless, our results suggest that endothelial damage might be prolonged in IVIG-treated patients. Control of endothelial damage in KD is critical.

Acquired hemophilia A: a frequently overlooked autoimmune hemorrhagic disorder.

Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed.

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.

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.