Idiopathic hypereosinophilic syndrome (HES) is charac- terized by an absolute eosinophil count greater than 1500 cells/mm 3 observed at least twice with a minimum interval of 4 weeks, multiorgan involvement, and pres- ence of tissue damage without an identifiable underlying cause . Renal involvement in HES varies from 7% to 36%; however, kidney injury mediated by thrombotic mi- croangiopathy (TMA) is rare . To the best of our knowledge, only two cases of idiopathic HES  and one case of myeloproliferative-variant HES  have been re- ported. None of the reported cases achieved normal kid- ney function after treatment. The pathophysiology of
Different etiologies have been described as a cause for EM, but the cause is frequently unknown. Well-estab- lished etiologies include hypersensitivity myocarditis due to medication (Table 1); acute necrotizing eosinophilic myocarditis (ANEM), usually with a fulminant course; hypersensitivity myocarditis associated with specific agents including smallpox, meningococcal C and hepati- tis B vaccines; hypereosinophilic syndrome; Loeffler ’ s endocarditis; tropical endomyocardial fibrosis; vasculitis such as Churg-Strauss; and malignancies including T- cell lymphoma and cancer of the lung and biliary tract [8,15].
hypereosinophilia (greater than 2600 cells/μl). His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL). Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic Hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor a, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality.
A thorough understanding of the idiopathic hypereosinophilic syndrome (IHES) and further optimization of diagnostic work-up procedures are warranted. We analyzed purified eosinophils from patients with IHES by next-generation whole- exome sequencing and compared DNA methylation profiles from reactive eosinophilic conditions to known clonal and suspected clonal eosinophilia. Somatic missense mutations in cancer-related genes were detected in three IHES patients. These included the spliceosome gene PUF60 and the cadherin gene CDH17. Furthermore, reactive eosinophilia samples could be differentiated from known- and suspected clonal eosinophilia samples based on 285 differentially methylated CpG sites corresponding to 128 differentially methylated genes. Using Ingenuity pathway analysis, we found that differentially methylated genes were highly enriched in functional pathways such as cancer, cell death and survival, and hematological disease. Our data show that a subset of IHES may be of clonal origin not related to the classical molecular aberrations of FGFR, PDGFRA/B, or T-cells, and that the initiating hits could be point mutations in a variety of genes, including spliceosome mutations or hypermethylated tumor suppressor genes. In addition, we identified a DNA methylation signature that is relevant for distinguishing clonal and suspected clonal eosinophilia from reactive eosinophilia per se, which may be useful in daily clinical work.
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or have signs or symptoms of gastrointestinal involve- ment . In a multicenter study including 188 HES pa- tients, it was found that 81% had been initially treated with steroids. The median dose of PSL or an equivalent steroid was 40 mg daily. Nearly 75% were on mainten- ance steroids for an extended period, with an average dose of 10 mg PSL daily. The duration of therapy ranged from 2 months to 20 years. Eighty-five percent of the pa- tients on steroid monotherapy had a partial or complete remission within 1 month of therapy initiation . In our case, although steroid therapy was very effective, it was necessary to continue 10 mg of oral PSL to ensure complete resolution because bleeding recurred when oral PSL was reduced to a lower dosage.
In summary, our experience, together with other published data, seem to support the hypothesis that HES is caused by a dysregulation of T lym- phocytes, resulting in persistent stimulation of hu- man eosinophilic granulopoiesis. Thus, a possible pathogenetic mechanism for the eosinophilia and subsequent organ damage in HES may be initially caused by an immune reaction triggered by a yet unknown antigenic stimulus. This in turn would lead to a direct release of eosinophil-activating cytokines (IL-2, IL-5, and eosinophil colony-stim- ulating factor) by activated T cells and would re- sult in a persistent T-cell–mediated stimulation of normal eosinopoiesis. In our patient, cyclosporine effectively halted this process. Cyclosporine seems to inhibit secretion of cytokines primarily by in- hibiting their production at the pretranslational level, 23 thereby shutting off the synthesis of IL-2
Balínt Syndrome is an acquired disorder manifesting in the inability to recognize several objects at once (simultagnosia), inaccurate visually guided limb movements despite intact motor function (optic ataxia) and the inability to make accurate voluntary saccades to visual targets despite demonstrating unrestricted range of eye movements (ocular motor apraxia). Here we report the first case of a patient presenting with Balínt Syndrome caused by a platelet-derived growth factor receptor A mutation (PDGFRA)-induced
Essentially pure preparations of normal density eosinophils obtained from patients with hypereosinophilic syndrome (HES) were stimulated with complement factor 5a (C5a), platelet-activating factor (PAF), FMLP and neutrophil-activating peptide (NAP-1/IL-8). Three responses were studied, the transient rise in cytosolic free calcium concentration ([Ca2+]i) (derived from indo-1 fluorescence), shape changes (measured by laser turbidimetry), and exocytosis of eosinophil peroxidase (EPO) (assessed by H2O2/luminol-dependent chemiluminescence). Responses were obtained with all four agonists, but C5a and PAF were by far more potent than FMLP and NAP-1/IL-8, which induced only minor effects. Pretreatment of the cells with pertussis toxin attenuated [Ca2+]i changes, EPO release and, to a lesser extent, shape changes, indicating that GTP-binding proteins of Gi-type are
In vivo DFO induced a septic shock in Yersinia-infected mice leading to death after 2 to 5 days, as suggested by the marked hepatocellular necrosis observed in these mice. Moreover, bac- terial counts were dramatically increased in infected organs (e.g., spleen) of DFO-treated mice compared to controls. More strikingly, HES-DFO-treated mice did not develop sep- tic shock after Yersinia infection, as indicated by the survival for more than a week after the infection. Nevertheless, prob- ably due to the release of DFO from HES-DFO and deposition of HES-DFO in certain organs such as the liver, Yersinia in- fection was finally exacerbated in some HES-DFO-treated mice, in which bacterial counts significantly increased com- pared to those in control mice. The majority of the HES-DFO- treated mice survived at least 14 days postinfection, and no bacteria could be detected in spleens of those mice.
The patients were randomly assigned to receive a 500 mL infusion of hydroxyethyl starch (HES; HES group) or saline (Saline group). Randomization was performed using a random number table. Standardized perioperative care was provided to all patients. An arterial line was placed in the radial artery and connected to a Vigileo-FloTrac system (software version 3.02, Edwards Lifesciences Corp, Irvine, CA, USA). General anesthesia was performed using target- controlled intravenous infusion of propofol (effect site concentration 2.0–4.0 g/mL) and continuous infusion of remifentanil (0.2–0.3 g/kg/min). Depth of anesthesia was controlled to maintain a bispectral index between 40 and 60. Rocuronium was administered to facilitate endotra- cheal intubation and to provide adequate muscle relaxation during surgery when necessary. Phenylephrine (50 µ g) was administered if necessary to maintain a mean arterial pressure .50 mmHg. In such case, the hemodynamic data were recorded at least 5 minutes after the phenylephrine administration to minimize the drug effect. Patients were mechanically ventilated with a tidal volume set between 8 and 10 mL/kg to achieve normocapnia, and positive end- expiratory pressure was applied at 5 cm H 2 O. A real-time 3D-TEE probe (X7-2t, Philips Medical Systems Japan,
After approval by the local ethics committee and written informed consent, blood samples from 14 healthy male volun- teers (22 to 61 years old) were obtained by a clean puncture of an antecubital vein and were anticoagulated by either sodium citrate (final concentration of 10.6 mM) or recom- binant hirudin (50 μg/mL). Blood samples were then diluted with HES 130/0.4 (Voluven 6%; Fresenius Kabi AG, Bad Homburg, Germany), HES 200/0.5 (HAES sterile 10%; Fre- senius Kabi AG) or sterile saline to obtain haemodilution rates of 10% and 40%. Thus, the final molar concentrations of HES 130/0.4 and HES 200/0.5 in the diluted blood samples were comparable. The samples were kept under gentle agitation for 15 minutes at 37°C prior to further analysis.
the origin of hydroxyethylstarch is waxy maize amylopectin, a highly branched polysaccharide similar to glycogen. the structure of HEs is determined by mainly 1-4 linkages of polymerized glucose and 1-6 branching linkages. thus the degradation of HEs by the serum _-amylase is elongated and its elimination from the blood circulation delayed. It was shown that the molecular weight (Mw) plays only a minor role in determining the pharmacological profile of HEs solu- tions . Rather the degree of molar substitution (Ms) and the substitution ratio at c2/c6 seem to determine the pharmacological profile of each HEs preparation .
All patients received mechanical calf compression thromboprophylaxis during surgery and 24 h postopera- tively. The fluid protocol included isotonic saline infu- sion as maintenance fluid (1.5–2.0 mL/kg/h). Bleeding (200–300 mL) was initially substituted with saline (1:2 bleeding to saline). Additional bleeding was substituted with HES (Venofundin® 60 mg/mL [6% hydroxyethyl, molecular weight (MW) 130 kDa, substitution 0.42, in saline solution, Braun, Melsungen Germany], 1:1 bleed- ing to HES), with a maximum dose of 30 mL/kg. HES was also used to keep mean arterial blood pressure (MAP) at >65 mmHg. Red blood cell transfusion was given when hemoglobin levels declined below 95–100 g/ L. Blood loss of more than 30 % of calculated blood vol- ume was substituted with red blood cells, fresh frozen plasma and platelet concentrates.
ponents and demonstrates full graphic representation of HES image and format. The first five key elements are shown one below the other. The HES image shows corre- sponding flooded energy contours (Fig. 3A). The PCG of a single heart beat shows S1, murmur and split S2 sounds in a consecutive order (Fig. 3B). Power plots of Figs. 3C and 3D illustrate the most significant energy components and their gradients. Fig. 3C demonstrates the integral power plot (energy integrated across all frequencies) and in Fig. 3D power is extracted at a pre-selected murmur fre- quency (shown as a horizontal line at the cross-hair, Fig. 3D), The power plot clearly shows the maximum ratio of murmur to S2 intensity to be equal to 32%, which is con- sistent with clinical impression of the murmur being of 2+/6 intensity . The instantaneous frequency plot (Figs. 4A and 4B) illustrates the start and end of each heart sound. The variation of frequency of these components is also seen. Clearly demonstrated is that the murmur fre- quency decreases, that S3 frequency is the lowest; and that S2 has two frequency components separated in time. The following three components are presented in Fig. 3E and represent:
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lead to the formation of articular cartilage and coordinate ossification and extension of the growth plate, as well as osteoblast differentia- tion . Overexpression of Hes could also accelerate osteogenesis and stimulate the expression of osteogenic marker genes, includ- ing osteopontin and type1 collagen . Recent studies show a prominent role of the Notch sys- tem in mesenchymal stem cell. Therefore, the Notchl-Hes signaling pathway could play a major role in AS development and could be a viable therapeutic target in AS treatment [22- 24]. In this study, we investigate the role of Notch1/Hes signaling pathway in AS pathogen- esis and explore the potential of this pathway for design of future prevention strategies.
Für unsere Studie wurden nach Genehmigung der Ethikkomission des Paul-Ehrlichs- Instituts 47 Patientinnen und Patienten randomisiert, bei denen perioperativ im Rahmen einer Zystektomie mit Anlage eines Ileumconduits oder einer Neoblase die Säure-Basen Parameter zu vier festgelegten Zeitpunkten bestimmt wurden. 21 Patienten wurde eine balancierte isoonkotische HES Lösung (HES 6% Volulyte der Firma Fresenius) und balancierte kristalloide Lösungen (Jonosteril) verabreicht. 26 Patienten bekamen perioperativ nahezu isoonkotisches Humanalbumin (Humanalbin 5% der Firma CSL Behring) und balancierte kristalloide Lösungen (Jonosteril). In beiden Gruppen wurde je bei Narkoseeinleitung, 1h nach Schnitt, 2h nach Schnitt sowie bei Operationsende die Konzentration von Natrium, Kalium, ionisiertem Kalzium, Chlorid, Phosphat, Albumin, Glukose und Hämoglobin, sowie der pH-Wert, der pCO 2 , pO 2 , BE, HCO 3 - , etCO 2 , Laktat,
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exhibited remarkably higher plasma level and extended clearance time from the plasma after injection in rats. Specifi- cally, the plasma concentrations of Morin were significantly higher in rats administered with Morin/HES-DOCA-NPs than those administered with Morin solution at all time points postinjection. In addition, free Morin was rapidly eliminated from plasma and hardly detected 5 h after administration of Morin solution. By contrast, Morin/HES-DOCA-NPs dem- onstrated significantly longer blood-circulation time than free Morin as Morin was still detectable 12 h postinjection. The relevant pharmacokinetic parameters were obtained using a two compartmental analysis (Table 2). AUC 0–t values were increased to 2.6 times in Morin/HES-DOCA-NPs formula- tions, compared to free Morin. Remarkably, the half-life of Morin (0.37 h) was significantly enhanced by more than fourfold by the incorporation of Morin into HES-DOCA NPs (1.52 h). These encouraging results suggest a possible higher therapeutic effect of Morin/HES-DOCA-NPs compared with Morin solution.
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Notch signaling regulates intestinal development, homeostasis and tumorigenesis, but its precise downstream mechanism remains largely unknown. Here we found that inactivation of the Notch effectors Hes1 , Hes3 and Hes5 , but not Hes1 alone, led to reduced cell proliferation, increased secretory cell formation and altered intestinal structures in adult mice. However, in Apc mutation-induced intestinal tumors, inactivation of Hes1 alone was sufficient for reducing tumor cell proliferation and inducing differentiation of tumor cells into all types of intestinal epithelial cells, but without affecting the homeostasis of normal crypts owing to genetic redundancy. These results indicated that Hes genes cooperatively regulate intestinal development and homeostasis and raised the possibility that Hes1 is a promising target to induce the differentiation of tumor cells.
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Hes-1 binds to the GADD45 α promoter and blockade of Hes-1 SUMOylation reduces Hes-1 binding to GADD45 α and decreases Hes-1 suppression of GADD45 α expression SUMOylation of transcription factors has been shown to affect their DNA-binding activity . Hes-1 SUMOyla- tion has not been reported previously, but Hes-1 was found to mediate cell survival upon amyloid-beta insult . However, the underlying mechanism of the protect- ive effect of Hes-1 is not fully understood. Here we aimed to examine whether Hes-1 SUMOylation may affect cell survival through alteration of Hes-1 binding to DNA promoter and downstream gene expression. A variety of genes are known to be responsive to Hes-1 . There are also many known stress sensors in the cell. In considering both factors we have carried out a preliminary study examining the effects of knockdown of Hes-1 on the expression of E2F1 and Growth Arrest and DNA Damage-inducible 45α (GADD45α). It turned out that Hes-1 had a more apparent effect in suppress- ing GADD45α expression. In addition, PIAS1 was found to negatively regulate the expression of GADD45α . Based on these results, we have therefore chosen GADD45α, an important stress sensor in the cell , for the present study. GADD45α transcript can be rapidly induced by many types of DNA-damaging agents including UV-irradiation , alkylation agent , and oxidizing agents such as H 2 O 2 [33-35]. Accumulative evidence indicates that
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Further to study the function of Hes-6 in breast cancer cells and to determine whether Hes-6 influences tumor growth, we performed xenograft studies in SCID/beige-immunodeficient mice. The T47D-Hes-6 or control cells were injected into the abdominal subcutaneous fat of 12-week-old female mice. Mice were killed on day 7 or 14, and the tumors were taken out, measured, and weighed (Figure 3a); representative pic- tures are shown in Figure 3d. Expression of Hes-6 caused a significant increase in both tumor weight (Figure 3a-1) and size (Figure 3a-2) at both 7 and 14 days. To measure the rate of proliferation in vivo, Ki67-immunohistochemistry was per- formed on the xenograft sections. Although the proliferation was high in both groups, the number of Ki67-positive cells was significantly higher in Hes-6yexpressing xenografts compared with controls (Figure 3e). RNA was extracted from the tumors and analyzed with real-time PCR. Whereas the endogenous level of Hes-6 in the T47D-control tumors was low, a strong induction of Hes6 was found in the T47D-Hes-6 tumors (Fig- ure 3b). In addition, E2F-1 was upregulated at the mRNA level in the Hes-6-expressing tumors compared with the controls (Figure 3c), in line with the in vitro experiments. Notably, how- Figure 1