Double filtration plasmapheresis: Review of current clinical applications.

Double filtration plasmapheresis (DFPP) is a semi-selective blood purification modality derived from the plasma exchange (PE) modality. In the DFPP treatment, two types of filters with different pore sizes are used: a plasma separator and a plasma component separator. Blood is separated into plasma and blood cells using a plasma separator. The separated plasma is fractionated into large and small molecular weight components by a plasma component separator. Large molecular weight components, including pathogenic substances, are discarded. Small molecular weight components, including valuable substances such as albumin, are returned to the patient. The advantage of DFPP is that the volume of replacement fluid can be significantly reduced compared to PE. By selecting the optimal pore size model for the plasma component separator, DFPP can be applied to various disorders. The clinical applications of DFPP are reviewed based on recent articles on metabolic disorders, organ transplants, rheumatic disorders, neurological disorders, and dermatologic disorders.

Modification of the Dialysate Port of Plasma Separators for Safe Blood Purification in Japan.

A fatal mix-up of a hemofilter with a plasma separator occurred in 2011. The close resemblance between the two blood purification columns commonly used in Japan posed a fundamental risk for such mix-ups. Both the in-hospital case investigation committee and the relevant academic societies have independently proposed the modifications of the dialysate port (D port) of the plasma separator to avoid this type of misuse. To make these devices foolproof, medical professionals, including physicians and clinical engineers, and members of the Medical Technology Association of Japan discussed measures to prevent this type of recurrence. Since new standards were soon to be issued by the International Organization for Standardization (ISO), the modifications were temporarily postponed. In September 2016, the ISO released new standards for small-bore connectors. The shape changes of the D port from the current slip-in type (ISO8637) to the Luer lock type (ISO80369-7) had been already approved by the Ministry of Health, Labor and Welfare of Japan by the end of November 2018, including a temporal use of a converter to connect the current type of D port to the new type of blood circuit. We must address the next issue that the new standard and the older standard coexist in the clinical setting, which may create a new risk.

Plasma separation using a membrane.

Plasma separation using a membrane is clinically used as plasmapheresis therapy, such as plasma exchange (PE), double-filtration plasmapheresis (DFPP), or plasma adsorption (PA) modalities. Plasma separation is performed either by centrifugation or by filtration, which involves a permeable hollow fiber membrane. A plasma separator with a hollow fiber membrane was first developed in Japan in the 1980s. It has been used for more than 30 years with continuous technical modifications. Treatment with a membrane-type plasma separator is a safe and well-established modality for many drug-resistant and/or refractory diseases. Currently, national health insurance covers plasmapheresis for ∼30 diseases in Japan. Membrane-type plasma separators are used not only in Japan but also in many other countries. Plasmapheresis treatments with a membrane-type plasma separator are an important alternative for patients with drug-resistant and/or refractory diseases at present and in the near future.

Immunoadsorption using Immusorba TR and PH.

Immusorba TR (IM-TR) and PH (IM-PH) were developed as immunoadsorbents from nonbiological materials as affinity ligands for removal of pathogenic substances. The immunoadsorbents in IM-TR and IM-PH are immobilized on a polyvinyl alcohol gel with tryptophan and phenylalanine, respectively, as a ligand. IM-TR is mainly clinically applied to autoimmune neurological diseases such as myasthenia gravis, Guillain-Barré syndrome, and multiple sclerosis. IM-PH is also applied to neurological diseases but mainly to rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. Many autoantibodies with different specificities have been found to have similar affinity for the ligand of Immusorba, and it is expected that Immusorba will be used against more diseases and help to elucidate the pathogenesis of diseases via identification of unknown pathogenic substances adsorbed to Immusorba.

Central line-associated bloodstream infection: is the hospital epidemiology of methicillin-resistant Staphylococcus aureus relevant?

We aimed to evaluate the risk factors, including the hospital epidemiology of methicillin-resistant Staphylococcus aureus (MRSA), for central venous line-associated and laboratory-confirmed bloodstream infections (CLA-BSI and LC-BSI, respectively). The risk factors examined included the age and sex of patients, whether or not they were in the surgery service, the number of days of central line (CL) placement, the monthly number of inpatients and those positive for MRSA, and whether the standard or maximal barrier precautions were observed at CL insertion. As the outcome factors, we selected CLA-BSI and LC-BSI, while precluding repeated isolation within 28 days. Of a total of 22,723 device days in 927 patients with CL placement, we observed 81 CLA-BSIs and 40 LC-BSIs, rates of 3.56 and 1.76 (/1000 device-days), respectively. Logistic regression analysis revealed a single significant factor, CL placement of more than 30 days, with odds ratios of 3.038 [95% confidence interval (CI) 1.733-5.326; P < 0.001] for CLA-BSI and 3.227 (95% CI 1.427-7.299; P = 0.005) for LC-BSI. Both BSIs included MRSA in seven events without temporal clusters. We conclude that the factor of long CL placement outweighs other risk factors, including the hospital epidemiology of MRSA.

Hydroxychavicol: a potent xanthine oxidase inhibitor obtained from the leaves of betel, Piper betle.

The screening of Piperaceous plants for xanthine oxidase inhibitory activity revealed that the extract of the leaves of Piper betle possesses potent activity. Activity-guided purification led us to obtain hydroxychavicol as an active principle. Hydroxychavicol is a more potent xanthine oxidase inhibitor than allopurinol, which is clinically used for the treatment of hyperuricemia.

Short-term efficacy of tacrolimus ointment and impact on quality of life.

BACKGROUND: Topical calcineurin inhibitor (TCI) was reported to be an effective therapeutic agent for patients with atopic dermatitis (AD), for not only improving clinical findings but also for reducing pruritus. Recently in Japan tacrolimus ointment (0.03%) as a TCI was approved for use in children aged > or =2 years. There have been no reports, however, on the impact of TCI on quality of life (QOL) in pediatric AD in Japan. The purpose of the present study was therefore to evaluate the efficacy of tacrolimus ointment (0.03%) in the short-term and the impact on patient QOL. METHODS: A total of 30 pediatric patients with AD, whose skin problems were not sufficiently controlled by mid-high potency topical glucocorticosteroids, were enrolled. Efficacy was assessed on score of cutaneous findings, pruritus, sleeping disorder, and QOL. RESULTS: Three patients discontinued because of skin burning (n = 1), generalized herpes infection (n = 1), and feeling of lack of efficacy (n = 1), leaving a final total of 27 patients who were evaluated. Significant improvements in clinical findings, pruritus, and sleeplessness were observed within 1 week of treatment and consequently each QOL category was also improved. These improvements continued for the duration of the study. CONCLUSIONS: Tacrolimus ointment therapy is rapidly effective for not only clinical symptoms (cutaneous findings, pruritus and sleeplessness) but also in QOL of AD pediatric patients aged > or =2 years.

Inhibitory effects of Citrus hassaku extract and its flavanone glycosides on melanogenesis.

The 50% ethanolic extract (CH-ext) obtained from the unripe fruit of Citrus hassaku exhibited significant tyrosinase inhibitory activity. The CH-ext showed antioxidant activity, such as superoxide dismutase (SOD)-like activity and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity. Activity-guided fractionation of the CH-ext indicated that flavanone glycoside-rich fractions showed potent tyrosinase inhibitory activity. Further examination revealed that the tyrosinase inhibitory activity and antioxidant activity of the CH-ext were attributable to naringin and neohesperidin, respectively. The CH-ext showed inhibition of melanogenesis without any effects on cell proliferation in cultured murine B16 melanoma cells after glucosamine exposure. The topical application of the CH-ext to the dorsal skin of brownish guinea pigs showed in vivo preventive effects against UVB-induced pigmentation.

Risk factors for central venous catheter-related bloodstream infection: a 1073-patient study.

We intended to evaluate the risk factors for catheter-related bloodstream infection (CR-BSI) with central venous (CV) catheters. For the hub of the CV line, we used three-way stopcocks in the first year of the study and closed needleless connectors (NCs) in the second year. Background factors included the age and sex of patients; the ward; the specialty service; the CV catheter and its days of placement; and the staff compounding the intravenous infusion, i.e., either nurses, who disinfect hands-free, or pharmacists using clean benches. Outcome factors included positive culture from the blood-related samples and the body temperature estimate. Of a total of 29 221 device-days in 1073 patients, positive cultures showed an overall incidence of 2.26 per 1000 device-days. Multivariate analysis showed a higher odds ratio of positive cultures for the ICU (odds ratio [OR], 4.415; 95% confidence interval [CI], 2.054-9.490]) and for CV catheter placement for more than 30 days (OR, 7.529; 95% CI, 4.279-13.247), but no significance for male sex (OR, 1.752; 95% CI, 0.984-3.119) or for pharmacists' compounding (OR, 2.150; 95% CI, 0.974-4.749). Univariate analysis showed no significance for the following factors: age more than 70 years (OR, 0.968; 95% CI 0.561-1.641), the surgery service (OR, 1.029; 95% CI, 0.582-1.818), double-lumen CV catheters (OR, 0.841; 95% CI, 0.465-1.521), or the NC (1.107; 95% CI, 0.673-1.821). We conclude that the theoretical benefit of the NC, the abolished dead space in the hub, contributed little to the outcomes of blood-related culture. The hands-free disinfection may have resulted in comparable odds ratios for the nurses and the pharmacists compounding the infusions.

Histamine release inhibitory activity of Piper nigrum leaf.

Oral administration of a methanolic extract of Piper nigrum leaf (PN-ext, 50, 200 and 500 mg/kg) showed a potent dose-dependent inhibition of dinitrofluorobenzene (DNFB)-induced cutaneous reaction at 1 h [immediate phase response (IPR)] after and 24 h [late phase response (LPR)] after DNFB challenge in mice which were passively sensitized with anti-dinitrophenyl (DNP) IgE antibody. Ear swelling inhibitory effect of PN-ext (50, 200 and 500 mg/kg, per os (p.o.)) on very late phase response (vLPR) in the model mice was significant but weaker than that on IPR. Oral administration of PN-ext (50, 200 and 500 mg/kg for 7 d) inhibited picryl chloride (PC)-induced ear swelling in PC sensitized mice. PN-ext exhibited in vitro inhibitory effect on compound 48/80-induced histamine release from rat peritoneal mast cells. Two lignans of PN-ext, (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2), were identified as major active principles having histamine release inhibitory activity.

Testosterone 5alpha-reductase inhibitory active constituents of Piper nigrum leaf.

Previously we reported that Piper nigrum leaf extract showed a potent stimulation effect on melanogenesis and that (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2) were isolated as active constituents. As a part of our continuous studies on Piper species for the development of cosmetic hair-care agents, testosterone 5alpha-reductase inhibitory activity of aqueous ethanolic extracts obtained from several different parts of six Piper species, namely Piper nigrum, P. methysticum, P. betle, P. kadsura, P. longum, and P. cubeba, were examined. Among them, the extracts of P. nigrum leaf, P. nigrum fruit and P. cubeba fruit showed potent inhibitory activity. Activity-guided fractionation of P. nigrum leaf extract led to the isolation of 1 and 2. Fruits of P. cubeba contain 1 as a major lignan, thus inhibitory activity of the fruit may be attributable to 1. As a result of further assay on other known constituents of the cited Piper species, it was found that piperine, a major alkaloid amide of P. nigrum fruit, showed potent inhibitory activity, thus a part of the inhibitory activity of P. nigrum fruit may depend on piperine. The 5alpha-reductase inhibitory activities of 1 and piperine were found for the first time. In addition, the P. nigrum leaf extract showed in vivo anti-androgenic activity using the hair regrowth assay in testosterone sensitive male C57Black/6CrSlc strain mice.

Mechanism of the melanogenesis stimulation activity of (-)-cubebin in murine B16 melanoma cells.

(-)-Cubebin showed a melanogenesis stimulation activity in a concentration-dependent manner in murine B16 melanoma cells without any significant effects on cell proliferation. Tyrosinase activity was increased at 24-72 h after addition of cubebin to B16 cells, and then intracellular melanin amount was increased at 48-96 h after the treatment. The expression levels of tyrosinase were time-dependently enhanced after the treatment with cubebin. At the same time, the expression levels of tyrosinase mRNA were also increased after addition of cubebin. Furthermore Western blot analysis revealed that cubebin elevated the level of phosphorylation of p38 mitogen-activated protein kinase (MAPK). SB203580, a selective inhibitor of p38 MAPK, completely blocked cubebin-induced expression of tyrosinase mRNA in B16 cells. These results suggested that cubebin increased melanogenesis in B16 cells through the enhancement of tyrosinase expression mediated by activation of p38 MAPK.

Different pattern of HSP47 expression in skeletal muscle of patients with neuromuscular diseases.

Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and secretion of procollagens, and its expression is increased in various fibrotic diseases. However, its involvement in muscle diseases is unknown. In this study, we analyzed HSP47 expression in muscular dystrophies and other muscle diseases. We found an overexpression of HSP47 in fibrous connective tissue and in the adjacent muscle membrane in various muscular dystrophies. However, in Ullrich congenital muscular dystrophy (UCMD), the overexpression of HSP47 was found only in the connective tissue, and not in the muscle membrane. The overexpression of HSP47 was found only in the muscle membrane in the case of active inflammatory myopathy. In particular, HSP47 was strongly expressed in the membrane of regenerating fibers. We found that HSP47 in the muscle membrane locates in the basement membrane with confocal microscopy. Our findings suggest that HSP47 may be involved in the repair or regeneration of muscle fibers in addition to the fibrotic change in the connective tissue.

Melanogenesis stimulation in murine B16 melanoma cells by Kava (Piper methysticum) rhizome extract and kavalactones.

Melanogenesis stimulation activity of aqueous ethanolic extracts obtained from several different parts of five Piper species, namely Piper longum, P. kadsura, P. methysticum, P. betle, and P. cubeba, were examined by using cultured murine B16 melanoma cells. Among them, the extract of P. methysticum rhizome (Kava) showed potent stimulatory effect on melanogenesis as well as P. nigrum leaf extract. Activity-guided fractionation of Kava extract led to the isolation of two active kavalactones, yangonin (2) and 7,8-epoxyyangonin (5), along with three inactive kavalactones, 5,6-dehydrokawain (1), (+)-kawain (3) and (+)-methysticin (4), and a glucosylsterol, daucosterin (6). 7,8-Epoxyyangonin (5) showed a significant stimulatory effect on melanogenesis in B16 melanoma cells. Yangonin (2) exhibited a weak melanogenesis stimulation activity.

Melanogenesis stimulation in murine b16 melanoma cells by umberiferae plant extracts and their coumarin constituents.

Melanogenesis stimulation activities of seven ethanolic extracts obtained from Umbelliferae plants used as Chinese crude drugs, namely the roots of Angelica dahurica BENTH. et HOOK., A. biserrata SHEN et YUAN, Notopterygium incisum TING, Heracleum lanatum MICHX., and H. candicans WALL., and the fruits of Cinidium monnieri (L.) CUSSON and C. formosanum YABE, were examined by using cultured murine B16 melanoma cells. Among them, the extract (5, 25 microg/ml) of H. lanatum showed a potent stimulatory effect on melanogenesis with significant enhancement of cell proliferation in a dose-dependent manner. The melanogenesis stimulatory effects of sixteen coumarins (1-16) isolated from the seven Umbelliferae crude drugs were also examined. Among them, linear-furocoumarins [psoralen (1), xanthotoxin (2), bergapten (3), and isopimpinellin (4)] and angular-furocoumarin [sphondin (13)] exhibited potent melanogenesis stimulation activity. From the view point of structure-activity relationships, it may be assumed that a linear-furocoumarin ring having a hydrogen and/or methoxyl group at 5 and 8 positions such as 1, 2, 3 and 4 was preferable for the melanogenesis stimulation activity. The introduction of a prenyl group into the furocoumarin ring was disadvantageous. Coumarin derivatives having a simple coumarin ring were inactive.

Melanogenesis stimulation in murine B16 melanoma cells by Piper nigrum leaf extract and its lignan constituents.

A methanolic extract from the leaves of Piper nigrum L. showed a significant stimulatory effect on melanogenesis in cultured murine B16 melanoma cells. Activity-guided fractionation of the methanolic extract led to the isolation of two known lignans, (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2), together with a new lignan, (-)-3-desmethoxycubebinin (3). Among these lignans, 1 and 2 showed a significant stimulatory activity of melanogenesis without any significant effects on cell proliferation.

Plasma separator Plasmaflo OP.

In recent years, polyethylene and polysulfone membranes have been used for plasma separation in Japan. The polyethylene membrane, manufactured by melt spinning method, has a sponge-like symmetric structure. The plasma separator Plasmaflo OP (Asahi Medical, Tokyo, Japan) with a polyethylene membrane shows excellent performance and safety for plasma separation. More than 20 indications for therapeutic plasmapheresis are reimbursed in Japan. Future development is expected in new membrane designs for new indications or advanced plasmapheresis methodologies.

Immusorba TR and PH.

Immusorba TR (IM-TR) and PH (IM-PH) were developed as adsorbents with non-biological materials as affinity ligands to remove pathogenic autoantibodies. The adsorbents of IM-TR and IM-PH are polyvinyl alcohol gel immobilized with tryptophan and phenylalanine as ligand, respectively. IM-TR is clinically applied for treatment of autoimmune neurological diseases such as myasthenia gravis and Guillain-Barre syndrome. IM-PH is used for not only neurological diseases such as GBS and multiple sclerosis but also collagen diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). As many autoantibodies with different specificities have been found to have similar affinities to the ligand of Immusorba, it is expected that Immusorba will be applied to more diseases and contribute to the clarification of the mechanisms of the development of diseases by the identification of adsorbed unknown pathogenic substances with Immusorba.