Polymethylmethacrylate Membrane Dialyzer: Historic but Modern.

Polymethylmethacrylate (PMMA) hollow fiber membranes are one of the synthetic polymer hollow fiber membranes used to the hollow fiber artificial kidney. A PMMA hollow fiber membrane (PMMA membrane) has unique properties including the uniform structure and the adsorption property. Hemodialyzers using PMMA membranes, Filtryzer®, were approved in Japan in 1977 and have been used worldwide for over 40 years and so is a historical hemodialyzer.Various types in Filtryzer® having different pore sizes are developed and used in the clinical field. Filtryzer® B3 is a low-flux dialyzer. Filtryzer® BK has three types having different pore sizes, and above all, BK-F has the largest pores in the Filtryzer® series. Filtryzer® BG has a more uniform membrane structure by using weak anionic polymers compared with the earlier Filtryzer® series to remove ß2-MG more. Filtryzer® NF is the latest Filtryzer® series and was developed as a dialyzer having improved antithrombogenicity compared with previous models and having protein adsorption property as the same with them. There have been many reports concerning Filtryzer® including improvement of patients' symptoms such as pruritus and nutrition on the advantages for dialysis patients. Although PMMA membranes are historic dialysis tools used for over 40 years, they are also modern dialysis membranes that have been updated to respond to dialysis therapy at those time.

Clinical course of disseminated intravascular coagulopathy-type amniotic fluid embolism: A report of three cases.

Amniotic fluid embolism (AFE) is a rare complication of pregnancy and its mortality rate is high. There have been few reports of AFE with presence of severe coagulopathy and incoagulable bleeding, and absence of cardiopulmonary symptoms or limited cardiopulmonary symptoms, followed by massive blood loss during delivery. Such cases have been referred to as disseminated intravascular coagulopathy-type AFE, and the characteristics of this condition have been presented previously. Here we report three cases that fulfilled the diagnostic characteristics of disseminated intravascular coagulopathy-type AFE.

Sonographic features of congenital infantile fibrosarcoma that appeared as a sacrococcygeal teratoma during pregnancy.

We experienced an extremely rare case of congenital infantile fibrosarcoma originating from the fetal sacrococcygeal region in pregnancy. At first, we suspected fetal sacrococcygeal teratoma; however, the following ultrasonography findings of the tumor complicated this diagnosis: (i) laterality; (ii) no cystic component; (iii) hypervascularity, with the feeding vessels not derived from the middle sacral artery; and (iv) a skin covering. The pathological findings indicated that the tumor was an infantile fibrosarcoma, not a teratoma. Thus, we believe that these sonographic features may aid the prenatal diagnosis of congenital infantile fibrosarcoma, which, in turn, may contribute to a better prognosis and may be useful for parental counseling.

Incidence of spontaneous twin anemia-polycythemia sequence in monochorionic-diamniotic twin pregnancies: Single-center prospective study.

AIM: The purpose of this study was to prospectively estimate the incidence of spontaneous twin anemia-polycythemia sequence (TAPS) in monochorionic-diamniotic twin pregnancies. METHODS: We prospectively examined umbilical cord hemoglobin (Hb) and reticulocyte count of consecutive monochorionic-diamniotic twin pregnancies delivered at Seirei Hamamatsu General Hospital from December 2006 to September 2013. We excluded cases of twin-twin transfusion syndrome, intrauterine fetal demise, and missing data (Hb and reticulocyte count missing from the medical record). TAPS was diagnosed using the postnatal criteria of intertwin Hb difference >8.0 g/dL and reticulocyte count ratio >1.7. Acute feto-fetal hemorrhage was defined as Hb difference >7 g/dL and reticulocyte count ratio <1.7. RESULTS: A total of 185 monochorionic-diamniotic twin pregnancies were included in this study. Three fulfilled the diagnostic criteria for postnatal TAPS, and one fulfilled the diagnostic criteria for acute feto-fetal hemorrhage. CONCLUSION: The incidence of spontaneous TAPS in monochorionic-diamniotic twin pregnancies was 1.6% (3/185) at Seirei Hamamatsu General Hospital.

Perinatal outcome of monochorionic twins with selective intrauterine growth restriction and different types of umbilical artery Doppler under expectant management.

OBJECTIVES: To evaluate the prognosis of monochorionic twins with selective intrauterine growth restriction (sIUGR), classified according to the type of umbilical artery Doppler, under expectant management. METHODS: The outcome of 81 cases with isolated sIUGR was evaluated according to a classification based on umbilical artery (UA) Doppler diastolic flow in the IUGR twin (I: present, II: constantly absent/reverse, III: intermittently absent/reverse). Selective feticide was not considered due to legal constraints. Perinatal outcomes included perinatal death and neurological outcome at 6 months of age. RESULTS: From 81 cases with the diagnosis of sIUGR, twin-twin transfusion was diagnosed in 18 cases. This left 63 cases, of which 23 were classified as type I (36.5%), 27 as type II (42.9%) and 13 as type III (20.6%). Intrauterine death occurred in 4.3% (1), 29.6% (8) and 15.4% (2) among IUGR twins, and 4.3% (1), 22.2% (6) and 0.0% (0) among larger twins. Neonatal death occurred in 0.0% (0), 18.5% (5) and 0.0% (0) among IUGR twins, and 0.0% (0), 11.1% (3) and 23.0% (3) among larger twins. Neurological abnormalities at 6 months were found in 4.3% (1), 14.8% (4) and 23.1% (3) in smaller twins and 0.0% (0), 11.1% (3) and 38.5% (5) in larger twins, respectively. Intact survival at 6 months was recorded in 91% (21), 37% (10) and 61% (8) in smaller twins and 95% (22), 55% (15) and 38% (5) in larger twins, respectively. CONCLUSION: The outcome in monochorionic twins with sIUGR and abnormal umbilical artery Doppler is poor under expectant management. Normal Doppler seems to be associated with a good prognosis.

Transitory increase in middle cerebral artery peak systolic velocity of recipient twins after fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

OBJECTIVE: It was the aim of this study to elucidate the clinical features of recipient twins with increased middle cerebral artery peak systolic velocity (MCA-PSV) after fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome. METHODS: Serial Doppler velocimetry of the MCA was performed in 30 recipient twins before and after FLP. Clinical data and perinatal outcome were compared between cases with and without increased MCA-PSV. RESULTS: Increased MCA-PSV was observed in 7 recipients (23.3%) within 14 days after FLP. MCA-PSV gradually decreased to <1.5 multiples of median in 6 recipients; however, 1 patient resulted in fetal demise subsequent to the demise of the co-twin. The incidences of fetal and neonatal demise and neurological morbidity were similar. No recipient was diagnosed as anemic at birth. CONCLUSIONS: The increase in MCA-PSV in recipients following FLP appeared to be generally transitory; this differs from twin anemia-polycythemia sequence.

Interferon-beta reduces the mouse liver fibrosis induced by repeated administration of concanavalin A via the direct and indirect effects.

Type I interferons (IFNs), IFN-alpha and IFN-beta, are widely used for treating chronic hepatitis C. Although retrospective studies have suggested that type I IFNs have direct antifibrotic effects, little is known about these mechanisms. The present study was designed to clarify the preventive mechanisms of type I IFNs in the progression of fibrosis for the establishment of a more effective therapy. A murine fibrosis model comprising immunological reactions was induced by the administration of concanavalin A (0.3 mg/body) into mice once a week for 4 weeks. Liver injury and the degree of fibrosis were determined by measuring the serum alanine aminotransferase activities and liver hydroxyproline contents with or without IFN-beta pretreatment. IFN-beta suppressed the hepatocellular injury and increased the hydroxyproline content induced by repeated concanavalin A injections, but had no effect on established fibrosis. Furthermore, IFN-beta reduced the expressions of transforming growth factor-beta, basic fibroblast growth factor, collagen type I A2 and tissue inhibitor of metalloproteinase 1 messenger RNAs, which are related to the progression of liver fibrosis. The IFN-beta reduced the liver injury and fibrosis induced by immunological reactions. These data suggest that type I IFNs suppress the progression of cirrhosis through inhibition of repeated hepatocellular injury and/or factors that promote the liver fibrosis induced by hepatitis virus infection.

Case with a Nonreassuring Fetal Status Induced by Massive Hematemesis due to Mallory-Weiss Tear That Required Emergency Cesarean Section at 38 Weeks' Gestation.

We describe a rare case of Mallory-Weiss tear with massive hematemesis at 38 weeks' gestation. A 35-year-old woman presented with epigastralgia followed by massive hematemesis. An emergency endoscopy indicated active pulsatile bleeding at the esophagocardial junction. Although an emergency endoscopic hemostasis was successful, late decelerations without acceleration on cardiotocogram were observed. Therefore, the patient underwent emergency cesarean section, along with blood transfusion, following the endoscopic hemostasis. The hemoglobin level just before the operation was 5.1 g/dL. We suspected that massive hematemesis induced maternal acute anemia and hypovolemia, which resulted in a nonreassuring fetal status. Hence, urgent endoscopic hemostasis, adequate blood transfusion, and emergency cesarean section were needed. Mallory-Weiss tear during the third trimester may have a possibility of massive hematemesis and urgent blood transfusion, emergency endoscopic hemostasis, and emergency cesarean section may be needed.

Effect of fatty acids on the phosphate binding of TRK-390, a novel, highly selective phosphate-binding polymer.

Phosphate binders are used for the treatment of hyperphosphatemia in hemodialysis patients with chronic kidney disease. Sevelamer, a phosphate-binding polymer, has been reported to bind bile acids or fatty acids and thereby decrease its phosphate-binding capacity. The novel phosphate binder TRK-390 is a poly (allylamine) polymer that has been shown to have enhanced phosphate selectivity, with low bile-acid-binding. In this study we evaluated the effect of fatty acids on the phosphate-binding capacity of TRK-390. In the absence of fatty acids and bile acids, the phosphate-binding capacity of TRK-390 was similar to that of sevelamer. In the presence of fatty acids and bile acids, the phosphate-binding capacity of TRK-390 was reduced to 83%; in contrast, that of sevelamer was reduced to 35%. TRK-390 and sevelamer showed a similar effect in lowering urinary phosphate excretion in normal rats fed a normal diet. However, urinary phosphate excretion of rats treated with TRK-390 was reduced by about one half of that obtained with sevelamer, when given with a high-fat diet that had a fat content similar to the diet of hemodialysis patients. TRK-390 was superior in terms of phosphate selectivity in the presence of fatty acids and bile acids in vitro, and the phosphate-binding capacity of TRK-390 in vivo was shown to be less affected by fat in comparison with that of sevelamer. Thus, TRK-390 is expected to be useful as a novel highly selective phosphate binder.

Structural and interaction analysis of glycoprotein VI-binding peptide selected from a phage display library.

Glycoprotein VI (GPVI) is a major collagen receptor on the platelet surface that recognizes the glycine-proline-hydroxyproline (GPO) sequence in the collagen molecule and plays a crucial role in thrombus formation. Inhibitors that block the interaction of GPVI with collagen have potential for use as antithrombotic drugs. For low molecular weight drug design for GPVI, it is essential to obtain precise structural and interaction information about GPVI-binding ligands. However, experimentally obtained structural and interaction information of small ligands, such as peptides, in the GPVI-bound state has not been reported. In this study, by screening a phage-displayed peptide library, we discovered a novel peptide ligand (pep-10L; YSDTDWLYFSTS) without any similarities to the sequence of collagen that inhibits GPVI-GPO binding. Systematic Ala scanning in surface plasmon resonance experiments and a saturation transfer difference NMR experiment revealed that Trp(6), Leu(7), Phe(9), and Ser(10) residues in the pep-10L peptide interacted with GPVI. Furthermore, the GPVI-bound conformation of the pep-10L peptide was determined using transferred nuclear Overhauser effect analysis. The obtained structure has revealed that the central part of pep-10L (Asp(5)-Phe(9)) has a helical conformation, the side chains of Trp(6), Leu(7), and Phe(9) form a hydrophobic side in the helix, and the Tyr(8) side chain faces the opposite direction from the hydrophobic side. Computational docking prediction has shown that the hydrophobic side of pep-10L sticks in the hydrophobic groove on the GPVI surface, which corresponds to the putative collagen-related peptide binding groove. These data could enable the structure-guided development of a small molecule GPVI antagonist.

A polysaccharide carrier to effectively deliver native phosphodiester CpG DNA to antigen-presenting cells.

Oligodeoxynucleotides containing unmethylated CpG sequences (CpG DNAs) activate the vertebrate innate immune system via toll-like receptor 9 (TLR-9). Although CpG DNA is a promising immunotherapeutic agent, its short circulation time in biological fluids due to nuclease is the major drawback. This paper proposes that a natural polysaccharide called schizophyllan (SPG) can be used as an effective CpG DNA carrier because SPG can complex with CpG DNA and the resultant complex shows the nuclease resistance of the bound DNA. In order to increase cellular uptake in vitro, we chemically attached spermine, cholesterol, arginine octamer, or RGD peptide to SPG. The complexes made of the chemically modified SPG and CpG DNA having a phosphorothioate (PS) or phosphodiester (PO) backbone led to increased secretion of cytokines of about 4- to 15-fold, compared with the uncomplexed dose. Furthermore, when PO CpG DNA was complexed with unmodified SPG, the IL-12 level increased by almost 3- to 11-fold compared with the naked dose. The PO CpG DNA/unmodified SPG complex data suggested that unmodified SPG might effectively deliver PO in vivo due to the electrically neutral nature of unmodified SPG. When the complexed CpG DNAs were injected intraperitoneally, a large amount of IL-12 production was observed compared with the uncomplexed material. Both in vivo and vitro assays indicated that the SPG complex may be of use for CpG DNA therapy.

Studies on the prevalence of human papillomavirus in pregnant women in Japan.

AIMS: In order to evaluate the prevalence of human papillomavirus (HPV) in the pregnant population in Japan. METHODS: We examined cervical swabs of 1,183 pregnant women for HPV DNA using a PCR-RFLP method during October, 2000 and February, 2001. The overall prevalence of HPV in 1,183 pregnant women was analyzed and stratified by age. RESULTS: The overall prevalence of HPV in pregnant women was 12.5% (148 of 1,183 cases). The prevalence in pregnant women younger than 25 years (22.6%, 28 of 124 cases) was significantly higher compared with that in pregnant women > or =25 years (11.3%, 120 of 1057 cases, P< 0.0005). CONCLUSIONS: The data indicate a significantly higher prevalence of HPV infection in younger pregnant Japanese women.

Synthesis and in vitro characterization of antigen-conjugated polysaccharide as a CpG DNA carrier.

Oligodeoxynucleotides containing unmethylated CpG sequences (CpG DNAs) are known as an immune adjuvant. CpG DNAs coupled with a particular antigen enabling both CpG DNA and antigen delivery to the same antigen-presenting cell have been shown to be more effective. Based on our previous finding that beta-(1-->3)-D-glucan schizophyllan (SPG) can be used as a CpG DNA carrier, here we present the synthesis of an antigen-conjugated SPG and the characterization of the conjugate. Ovalbumin (OVA, 43 kDa) was used as a model antigen, and two OVA were conjugated to one SPG molecule (M(w) = 150,000), denoted by OVA-SPG. Circular dichroism and gel electrophoresis showed that OVA-SPG could form a complex with a (dA)(40)-tailed CpG DNA at the 3' end (1,668-(dA)(40)). When OVA-SPG was added to macrophages (J774.A1), the amount of the ingested OVA-SPG was increased compared with that of OVA itself, suggesting that Dectin-1 (proinflammatory nonopsonic receptor for beta-glucans) is involved to ingest OVA-SPG. Furthermore, the complex of the conjugate and DNA was co-localized in the same vesicles, implying that OVA (antigen) and CpG DNA (adjuvant) were ingested into the cell at the same time. This paper shows that OVA-SPG can be used as a CpG DNA carrier to induce antigen-specific immune responses.

A novel, selective, and orally available antagonist for CC chemokine receptor 3.

CC chemokine ligand 11 (CCL11/eotaxin) and other CC chemokine receptor 3 (CCR3) ligands (CCL24/eotaxin-2, CCL26/eotaxin-3, CCL13/monocyte chemotactic protein-4, etc.) play important roles in the chemotaxis and activation of eosinophils and other CCR3-expressing cells (basophils, mast cells, and CD4(+) T helper 2 cells) in allergic inflammation incidents, including asthma and rhinitis. A newly synthesized compound, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-{1-[(5-hydroxy-3-methylpyridin-2-yl)carbonyl]piperidin-4-ylidene}-acetamide hemifumarate (YM-355179), inhibited the binding of CCL11 and CCL5/regulated on activation normal T cell expressed and secreted to CCR3-expressing B300-19 cells with IC(50) values of 7.6 and 24 nM, respectively. In contrast, YM-355179 did not affect the binding of CCL5 to CCR1 or CCR5. In functional assays, YM-355179 inhibited CCL11-induced, intracellular Ca(2+) influx, chemotaxis, and eosinophil degranulation with IC(50) values of 8.0, 24, and 29 nM, respectively. YM-355179 did not, however, affect any CC chemokine receptor (CCR1, CCR2, CCR4, or CCR5)-mediated Ca(2+) influx signals. Furthermore, oral administration of YM-355179 (1 mg/kg) inhibited CCL11-induced shape change of whole blood eosinophils in cynomolgus monkeys. Intravenous injection of YM-355179 (1 mg/kg) also inhibited eosinophil infiltration into airways of cynomolgus monkeys after segmental bronchoprovocation with CCL11. These results indicate that YM-355179 is a novel, selective, and orally available CCR3 antagonist with therapeutic potential for treating eosinophil-related allergic inflammatory diseases.

A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA.

The innate immune system recognizes nucleic acids during infection or tissue damage; however, the mechanisms of intracellular recognition of DNA have not been fully elucidated. Here we show that intracellular administration of double-stranded B-form DNA (B-DNA) triggered antiviral responses including production of type I interferons and chemokines independently of Toll-like receptors or the helicase RIG-I. B-DNA activated transcription factor IRF3 and the promoter of the gene encoding interferon-beta through a signaling pathway that required the kinases TBK1 and IKKi, whereas there was substantial activation of transcription factor NF-kappaB independent of both TBK and IKKi. IPS-1, an adaptor molecule linking RIG-I and TBK1, was involved in B-DNA-induced activation of interferon-beta and NF-kappaB. B-DNA signaling by this pathway conferred resistance to viral infection in a way dependent on both TBK1 and IKKi. These results suggest that both TBK1 and IKKi are required for innate immune activation by B-DNA, which might be important in antiviral innate immunity and other DNA-associated immune disorders.