Synthesis,characterization and photoreaction of side-chain liquid-crystalline polymers and copolymers comprising alkenyloxy-biphenyl mesogen

Photoreactive (meth)acrylate monomers having mesogenic groups based on 4-hexyloxy-4′-(3-methyl-2-butenyloxy)biphenyl and 4-hexyloxy-4′-(2-butenyloxy)biphenyl were synthesized. Methacrylate monomers ( 3c, d ) and acrylate monomer having 3-methyl-2-butenyloxy group ( 3b ) were polymerized by free radical mechanism; the acrylate monomer having 2-butenyloxy group ( 3a ) caused gelation during the polymerization. To obtain photoreactivity, 4-benzoylphenyl (meth)acrylates were radically copolymerized with monomers 3b and 3d . Thermal behavior of (co)polymers was determined by differential scanning calorimetry, polarized optical microscopy and temperature-controlled X-ray analysis. (Co)polymers showed liquid-crystalline behaviour with nematic and smectic phases. UV-irradiation was used to photochemically crosslink copolymer films, and the resultant films were insoluble in organic solvents. The uniaxially oriented copolymer thin film was photo-crosslinked and showed thermally stable orientation.     

Effects of fasting on biperiden pharmacokinetics in the rat

The effects of fasting on the pharmacokinetics of biperiden in rats were examined. Total clearance of biperiden was greater than 90% ascribable to hepatic clearance and was essentially blood-flow dependent. The number of compartments in the preferred pharmacokinetic model of biperiden changed from three (for normal rats) to two (for fasted rats). The smaller mean residence time (MRT) values found for fasted rats were attributable to decreases in distribution volume. Biperiden showed much higher lipophilicity than haloperidol, thiopental, and hexobarbital, and its tissue-to-plasma partition coefficient in adipose tissue was 20-fold higher than that in muscle. The influence of changes in volumes of adipose tissue and muscle on distribution volume (Vdss/BW) was evaluated from tissue-to-plasma partition coefficients. The value of Vdss/BW was predicted to decrease with decrease of adipose tissue, and to increase with decrease of muscle tissue. These results suggest that the observed decrease of Vdss/BW in fasted rats reflects reduced capacity to trap biperiden in the body, especially in adipose tissue. Possible clinical implications of these results are discussed.     

Liberation of serotonin from rabbit blood platelets by bacterial cell walls and related compounds.

A study was made on the activity of various bacterial cell walls and peptidoglycans to liberate serotonin from rabbit blood platelets. All of the test cell walls or peptidoglycans prepared from 27 strains of 21 bacterial species were shown to cause a marked release of serotonin, regardless of differences in types of peptidoglycan and non-peptidoglycan moieties and in some biological properties. The assay made with the water-soluble "digests" of Staphylococcus epidermidis cell wall peptidoglycans, which were prepared by use of appropriate enzymes, revealed that a polymer of peptidoglycan subunits (a disaccharide-stempeptide) was definitely active in the release of serotonin, but a structural unit monomer was inactive. Among a variety of synthetic muramylpeptides and their 6-O-acyl derivatives, only 6-O-(3-hydroxy-2-docosylhexacosanoyl)-N-acetylmuramyl-L-alanyl-D-isoglutaminyl- L-lysyl-D-alanine was found to hold a strong serotonin-liberating activity.     

Contractile effects of bacterial cell walls, their enzymatic digests, and muramyl dipeptides on ileal strips from guinea pigs.

Cell walls isolated from four bacterial species (Streptococcus pyogenes, Lactobacillus plantarum, Streptomyces gardneri, and Nocardia corynebacteriodes), which exhibited the adjuvant effect of stimulating cellular and humoral immune responses against ovalbumin in guinea pigs, caused the slow-starting and long-lasting contraction of guinea pig ileal strips suspended in Tyrode solution. In contrast to these cell walls active in immunoadjuvancy, those isolated from five bacterial species (Micrococcus lysodeikticus, Staphylococcus epidermidis, Arthrobacter atrocyaneus, Corynebacterium insidiosum, and Ampullariella regularis), which lacked immunoadjuvancy at least in intact walls, caused no or very weak contraction of the ileal strips. Further study demonstrated that both a monomer and a polymer of disaccharide-stem peptides, which were obtained by enzymatic degradation of S. epidermis cell wall peptidoglycans, displayed similar contractile effects. It was finally revealed that guinea pig ileum strips showed a definite contractile response to N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and 6-O-stearoyl- and 6-O-(2-tetradecylhexadecanoyl)-MDPs, but not to their analogs, whose C-terminal amino acid was L-isoglutamine or D-isoasparagine in place of D-isoglutamine and which lacked adjuvancy. 6-O-(3-Hydroxy-2-docosylhexacosanoyl)-MDP, on the other hand, caused a slow and lasting relaxation of the ileum strips, but its L-isoglutamine and D-isoasparagine analogs did not.     

Bone morphogenic protein-2 signaling in human disc degeneration and correlation to the Pfirrmann MRI grading system

BACKGROUND CONTEXTBack and neck pain secondary to disc degeneration is a major public health burden. There is a need for therapeutic treatments to restore intervertebral disc (IVD) composition and function.PURPOSETo quantify ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression in IVD specimens collected from patients undergoing surgery for disc degeneration, to correlate ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression in IVD specimens to the 5-level Pfirrmann MRI grading system, and to compare ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression between cervical and lumbar degenerative disc specimens.STUDY DESIGNAn immunohistochemical study assessing ALK3, BMP-2, pSMAD1/5/8, and MMP-13 expression levels in human control and degenerative IVD specimens.METHODSHuman IVD specimens were collected from surgical patients who underwent discectomy and interbody fusion at our institution between 1/2015 and 8/2017. Each patient underwent MRI prior to surgery. The degree of disc degeneration was measured according to the 5-level Pfirrmann MRI grading system. Patients were categorized into either the 1) control group (Pfirrmann grades I-II) or 2) degenerative group (Pfirrmann grades III-V). Histology slides of the collected IVD specimens were prepared and immunohistochemical staining was performed to assess ALK3, BMP-2, pSMAD1/5/8, and MMP-13 expression levels in the control and degenerative specimens. Expression levels were also correlated to the Pfirrmann criteria. Lastly, the degenerative specimens were stratified according to their vertebral level and expression levels between the degenerative lumbar and cervical discs were compared.RESULTSFifty-two patients were enrolled; however, 2 control and 2 degenerative patients were excluded due to incomplete data sets. Of the remaining 48 patients, there were 12 control and 36 degenerative specimens. Degenerative specimens had increased expression levels of BMP-2 (p=.0006) and pSMAD1/5/8 (p<.0001). Pfirrmann grade 3 (p=.0365) and grade 4 (p=.0008) discs had significantly higher BMP-2 expression as compared to grade 2 discs. Pfirrmann grade 4 discs had higher pSMAD1/5/8 expression as compared to grade 2 discs (p<.0001). There were no differences in ALK3 or MMP-13 expression between the control and degenerative discs (p>.05). Stratifying the degenerative specimens according to their vertebral level showed no significant differences in expression levels between the lumbar and cervical discs (p>.05).CONCLUSIONSBMP-2 and pSMAD1/5/8 signaling activity was significantly upregulated in the human degenerative specimens, while ALK3 and MMP-13 expression were not significantly changed. The expression levels of BMP-2 and pSMAD1/5/8 correlate positively with the degree of disc degeneration measured according to the Pfirrmann MRI grading system.CLINICAL SIGNIFICANCEBMP-SMAD signaling represents a promising therapeutic target to restore IVD composition and function in the setting of disc degeneration.     

Effect of chemotherapy combined with caffeine for osteosarcoma

Summary Nine patients with osteosarcoma were treated by chemotherapy combined with caffeine and surgery. All primary tumors showed complete histological response to preoperative chemotherapy consisting of three intraarterial infusions of cisplatin and caffeine without/with doxorubicin and two systemic high-dose methotrexate combined with vincristine. Limb-salvage surgery was performed in eight patients with marginal procedure, which led to the preservation of good limb function. Below-knee amputation was done in one patient with calcaneal osteosarcoma. There has been neither local recurrence nor lung metastasis in seven patients with conventional osteosarcoma during a median follow-up period of 28 months. Lung metastases leading to death were observed in one patient with small-cell osteosarcoma despite complete destruction of the primary tumor by preoperative chemotherapy. Chemotherapy combined with caffeine administration deserves further extensive and large-scale study in osteosarcoma.     

Twins with Neonatal Pemphigus Vulgaris Born to a Mother with Pemphigus Vulgaris: A Case Report

Abstract: Dichorionic diamniotic twins were born at 37 weeks of gestation by cesarean section to a 34‐year‐old primigravid Japanese woman because the first twin was in breech presentation. The mother had been diagnosed with pemphigus vulgaris prior to her pregnancy. In addition to a high antidesmoglein 3 autoantibody titer, flaccid bullae and erosions on both of the twins’ lips and in their oral cavities at 13 days of age led to the diagnosis of neonatal pemphigus vulgaris. This case highlights the need for awareness that pemphigus vulgaris may not occur immediately after birth.     

Bioinspired mineralization and cell adhesion on surface functionalized poly(vinyl alcohol) films

Poly(vinyl alcohol) (PVA) films, when surface functionalized by phosphorylation, induced biomimetic nucleation and growth of calcium phosphate in a simulated physiological environment. The surface phosphorylation on PVA was ensured by attenuated total reflectance infrared spectroscopy. The morphology of the calcium phosphate phase grown on surface-phosphorylated PVA (PPVA) was analysed using scanning electron microscopy coupled with an energy-dispersive X-ray detector. The primary nucleation of calcium phosphate occurs in 3 days and secondary nucleation occurs after 10 days. The energy-dispersive X-ray analysis shows that the Ca/P ratio of the coating increases with time of exposure to the simulated physiological fluid and reaches 1.67 at 10 days. The PPVA supports in vitro cell adhesion and promotes in vitro biomineralization in the presence of cells, evaluated using human osteosarcoma cells.     

Long-term levothyroxine treatment decreases the oral bioavailability of cyclosporin A by inducing P-glycoprotein in small intestine

We have noticed that the trough level of blood concentration of cyclosporin A (CyA) tends to be lower in patients receiving long-term oral levothyroxine (LTX) than in patients not receiving LTX. We confirmed this clinical observation in experiments using Wistar rats orally given LTX (8 microg/kg) or saline (control) for 3 weeks, followed by CyA (10 mg/kg). The LTX treatment had little effect on the blood concentrations of CyA after i.v. administration, whereas they were decreased significantly after p.o. administration. After p.o. administration, the value of the area under the blood concentration-time curve from 0 to 24 hr and the bioavailability of CyA in the LTX group were decreased to only about one-fifth and a quarter of those in the control group, respectively. After treatment with LTX, the expression levels of mdr1a, mdr1b and CYP3A2 mRNAs in the duodenum were markedly increased to about twice the control, but in jejunum, ileum and liver the expression levels were little changed. These findings suggest that the absorption of CyA, which occurs mainly from the upper intestine, is reduced as a result of efflux transport via P-glycoprotein induced by LTX. In conclusion, careful monitoring of CyA levels is required in the event of LTX administration to patients receiving immunotherapy with CyA.