Some remarks about the moduli of monotonicity are presented. Formulas for the characteristics of monotonicity in Banach lattices are given. Lower and upper estimates of the (lower) modulus of ...monotonicity of Orlicz spaces equipped with the Luxemburg norm using Simonenko and Lindberg indices as well as some other two parameters for the generated Orlicz function are given. The characteristic of monotonicity
ε
0
,
m
(
L
Φ
)
of Orlicz spaces endowed with the Luxemburg norm is estimated from below and another characteristic of monotonicity
ε
¯
0
,
m
(
L
Φ
)
of the spaces is computed.
Transcription factor EKLF (Erythroid Krüppel-Like Factor) belongs to the group of Krüppellike factors, which regulate proliferation, differentiation, development and apoptosis of mammalian cells. ...EKLF factor is present in erythroid cells, where it participates in regulation of hematopoiesis, expression of genes encoding transmembrane proteins (including blood group antigens), and heme biosynthesis enzymes. It is also a key factor in downregulation of γ-globins and activation of β-globin gene expression. The EKLF factor consists of two domains: proline-rich transactivation domain and DNA-binding domain containing three zinc finger motifs, which recognize DNA. EKLF can act as a transcription activator (for example in the case of β-globin gene) or repressor, which depends on the type of posttranslational modification (phosphorylation, SUMOylation, ubiquitination and acetylation). Mutations in the gene encoding EKLF may cause hemoglobinopathies, such as hereditary persistence of fetal hemoglobin and β-thalassemia intermedia, and congenital dyserythropoietic anemia type IV, which is a hematopoietic disorder. These changes may impede invasion of red blood cells by malaria merozoites and cause faster removal of invaded erythrocytes. In addition, mutations in KLF1 may decrease the number of erythrocyte surface antigens that belong to blood group systems such as MN, P1PK, Lutheran, Duffy, Diego and OK. Such antigens can be receptors for protozoans (such as Plasmodium falciparum or Plasmodium vivax), bacteria (like uropathogenic strains of Escherichia coli, Neisseria meningitidis), and toxins (Shiga toxins), which may cause several dangerous diseases including malaria, pyelonephritis, hemorrhagic colitis, hemolytic uremic syndrome (HUS) and meningitis. Here, we propose a hypothesis on possible liaisons between mutations in the gene encoding EKLF and resistance to pathogens.
To analyze the effect of perioperative decorin in an experimental setting of glaucoma filtration surgery.
Glaucoma filtration surgery, similar to that performed in clinical practice, was performed on ...35 chinchilla rabbits (ChBB:CH). The animals received a unilateral subconjunctival injection of decorin (40-100 microg) or the vehicle alone before surgery and at different time intervals thereafter. Antifibrotic efficacy was established by clinical response and histologic examination. The animals were killed on day 14, and the eyes processed for histology.
Both the vehicle and the decorin solution were well tolerated. No adverse effects such as inflammation or blurring of the optical media were observed. Conjunctival scarification occurred within 1 week in the control groups but was suppressed in the experimental groups. The intraocular pressure correlated with the fibrotic process and reached normal levels within 7 days after surgery in control animals, but remained significantly (P <0.001) reduced in the experimental groups. Histologic examination of the surgical area 14 days after surgery disclosed massive fibrosis in the control animals, but little deposition of extracellular matrix in the experimental groups.
The data of this pilot study suggest that perioperative subconjunctival decorin applications significantly affect conjunctival scarring and surgical outcome of glaucoma filtration treatments in rabbits.
: Endotamponade of the vitreous body with silicone oil is a common procedure, being the basis of many vitreoretinal surgeries. However, emulsification may happen, which is a clinically relevant ...adverse event of silicone oil use.
: This review provides a thorough analysis of the emulsification process. It focuses on describing factors affecting this event as well as its possible subsequent complications.
: The viscosity of silicone oil, the duration of emulsification, the status of the lens and many other factors have an influence on the onset and intensity of emulsification. This phenomenon carries several risks for operated eyes such as increased intraocular pressure, keratopathy or structural changes to the retina.
: The use of modern imaging techniques, especially optical coherence tomography, enables faster detection of the emulsification process. This allows for an adequate clinical response and more accurate follow-up of the patient.
Inhibitor formation is the most serious complication of FVIII replacement therapy for hemophilia A. The long-standing “danger theory” posits that inhibitors may form as part of collateral damage from ...immune response to a primary challenge such as an infection or vaccination. Innate immune signaling, for example through Toll-like receptors (TLRs), could be one way of triggering or reinforcing unwanted immune responses. However, the danger hypothesis has been contradicted by recent reports showing no increase in inhibitor formation in boys and animal models with hemophilia when FVIII was administered concurrently with vaccines. The aim of this study was to elucidate the influence of TLR9 signaling on FVIII inhibitor formation in hemophilia A mice.
Hemophilia A (F8e16-/-) B6/129 mice were co-injected IV with FVIII (1.5 IU) and ODN-1826 (a class B CpG oligodeoxynucleotide, 50 µg), which is a TLR9 agonist. Control mice were naïve or received FVIII only. Blood samples and spleens were collected for Bethesda assay and flow cytometry analysis 3h, 24h, 2, 3 and 7 days or 2, 4, 6 and 8 weeks after a single or repeated once-weekly injections.
After four weeks, mice co-injected with FVIII and ODN-1826 (n=4) showed ~15-fold higher inhibitor titers (median 2667 BU/mL) than mice injected with FVIII only (median 181.4 BU/mL; n=15). We also found significantly higher T follicular helper (Tfh; CD4+CXCR5+PD1+Bcl6―) F (7, 96) = 9.801, p<0.0001 and Germinal Center (GC) B cell numbers (CD19+GL7+CD95+) F (6, 92) = 11,53, p<0.0001 in the spleen after 4, 6 and 8 weeks of co-injections, with the Tfh numbers being 1.3-, 12.2- and 1.65-fold, while GC B cell numbers being 2.9-, 5.3- and 1.1-fold higher, respectively, compared to mice injected with FVIII only. GC B cell numbers correlated with inhibitor titers r(31)=0.52, p=0.002.
We also investigated dendritic cell (DC) responses after a single injection of FVIII or co-injection with ODN-1826. We found increased numbers of monocyte-derived DCs (moDCs; CD11chighMHCII+CD11b+ CD64+MAR-1+) in the co-injected group at all time points (3, 24, 48, 72 hours and 1 week after a single injection; n=4-5 per group) with the peak number (~10-fold higher compared to naïve mice; p=0.0002) being reached 72 hours and remaining similarly elevated at 1 week. However, levels of activation markers CD86 and MHCII on moDCs in both injected groups were not significantly elevated. The moDC numbers were also ~2.5-fold higher in the FVIII only group than in naïve animals at one week post-administration, but the difference was not statistically significant. Conversely, exposure to FVIII with or without ODN-1826 did not significantly affect the number of CD8α+CD11b- DCs, but this subset showed >2-fold upregulation of both CD86 and MHCII in the co-injected group 3h and 24h after injection (n=5-11, p<0.01). We further found increased numbers of plasmacytoid DCs (pDCs; CD11c+CD11b―PDCA+) but the difference was significant only in the co-injected group at d1 and d7 after injection (~2-fold higher than the naïve group; n=4-16 per group, p<0.05). This DC subset also showed upregulated CD86 and MHCII levels ~2-fold in the co-injected group, with difference between CD86 levels showing significance (p=0.0024). We next examined an interferon signature in pDCs by intracellular cytokine staining and found that the cells from co-injected mice had ~2-fold higher levels of IFNβ (p=0.0001, n=5 per group).
We propose that TLR9 stimulation enhances FVIII inhibitor formation in hemophilia A mice through recruitment and/or activation of conventional CD8α+ and plasmacytoid dendritic cells. The narrowing differences in Tfh and GC B cell numbers between the FVIII only and ODN-1826 co-injected groups at week 8 suggest that TLR9 stimulation accelerates GC formation in response to FVIII, which otherwise may reach a similar magnitude, but it takes longer. Also, our results suggest that it may be premature to put the danger theory to rest. The outcome of an immune challenge may vary depending on which innate immune receptor is concurrently stimulated. Notably, all vaccinations tested in the animal study showing no link to inhibitor formation were against pathogens with genomes composed of single-stranded RNA (measles, mumps, rubella and influenza viruses), which does not activate TLR9. Therefore, the impact of vaccination against single-stranded DNA pathogens that can stimulate TLR9, such as VZV, may be worth further investigation.
Herzog:Takeda Pharmaceuticals: Patents & Royalties.
Ludwik Hirszfeld (1884–1954) was a Polish physician, immunologist and microbiologist. Together with Emil von Dungern, he showed that blood groups are heritable traits and established the terminology ...of the ABO blood group system. He discovered A1 and A2 blood groups, and showed for the first time, in a large‐scale population study, that blood group frequency differs between populations. During World War I, he volunteered as an army physician. In the interwar period, he helped to create the National Institute of Hygiene in Warsaw and was instrumental in developing transfusion centres in Poland. During World War II, which he barely survived, he co‐organized secret medical courses in the Warsaw Ghetto and played a major role in containing the typhus epidemic that ran rampant there since 1941. After the war, he was the first in Poland to put the theory of serological conflict between mother and foetus into clinical practice, saving the lives of almost 200 children by introducing exchange transfusions.
Triamcinolone acetonide (TA) has been proposed as an adjuvant to pars plana vitrectomy with silicone oil for the surgical treatment of proliferative vitreoretinopathy and proliferative diabetic ...retinopathy. However, to date no data about the distribution and pharmacokinetics of lipophilic TA injected into silicone oil have been reported.
An artificial vitreous space chamber was filled with silicone oil. TA was either injected or dispersed into silicone oil. TA release using a continuous flow model was measured spectrophotometrically. To determine the antiproliferative or cytotoxic effect of the released TA, monolayer cultures of retinal pigment epithelial cells (ARPE19) and retinal ganglion cells (RGC5) were used. Bromodeoxyuridine incorporation, MTT assay, and scanning electron microscopy were performed.
Injected TA sank slowly through the silicone oil and started to sediment below the silicone oil bubble shortly after injection. After the simulated intravitreal injection, no TA could be retrieved from the silicone oil bubble. In contrast, when a suspension of silicone oil and TA was prepared before injection, stable noncytotoxic amounts of TA (25 microg/mL) could be retrieved for up to 90 days. After mere injection (without previous suspension in silicone oil), the sedimented TA crystals showed a pronounced cytotoxic effect.
Intravitreally injected TA does not mix with silicone oil. TA crystals that sediment at the lower border of a silicone oil bubble may be harmful to retinal cells. A suspension of TA in silicone oil may exhibit safer extended release over several days.
PURPOSE:Amniotic membrane transplantation has become an important treatment option for corneal surface reconstruction. However, suture fixation of the transplant has various disadvantages like ...corneal irritation, scarring, graft loss due to membrane shrinkage, and the need for subsequent suture removal. Replacement of sutures by bioadhesives might be an advantageous alternative. This controlled study was designed to evaluate a new sutureless technique for amniotic membrane fixation onto the corneal surface by using fibrin glue.
METHODS:Standardized disks of cryopreserved amniotic membranes were transplanted onto the deepithelialized cornea of 12 rabbits using either conventional suture fixation or a new fibrin glue technique. The rabbits were followed-up with slit-lamp examination and fluorescein staining until epithelialization was completed. Consecutively, the rabbits were killed and the eyes processed for histology and immunohistochemistry for cytokeratin-3.
RESULTS:All membranes of both groups stayed in place throughout the follow-up time and showed a progressive graft epithelialization that was completed after 12 days. Whereas suture-fixated membranes showed progressive tissue shrinkage, fibrin-glued sheets remained unaltered. In the bioadhesive group, histology revealed a smooth fibrin layer in the graft-host interface and a continuous, stratified layer of cytokeratin-3 expressing corneal epithelial cells on the membrane surface. In contrast, suture-fixated membranes showed contracted and prominent membrane edges with epithelial ingrowth into the submembrane interface.
CONCLUSION:Our results demonstrate the general feasibility of reproducible and reliable sutureless amniotic membrane fixation onto the corneal surface in rabbits. Stable adherence is maintained until epithelialization is completed. The sutureless technique gives sufficient manipulation time for the sheet before the final cross-linking process is completed. Furthermore, several advantageous characteristics could be demonstrated as increased biocompatibility, better epithelialization pattern and the lack of membrane shrinkage.
Diabetic macular edema (DME) is responsible for three-quarters of vision-loss cases in diabetic eye disease. In most cases, early treatment by laser photocoagulation can only stabilize vision. ...Glucocorticoids have been used as a local pharmacological treatment in DME when the inflammation seems to have a pathological background.
The aim of the study was to establish the effectiveness and safety of intravitreal triamcinolone injections in the treatment of DME.
Twenty mg intravitreal injections of triamcinole acetonide (IVTA) were applied to 110 DME patients after ineffective laserphotocoagulation or as an initial treatment. Best corrected visual acuity (BCVA) for distant and near vision, central retinal thickness and intraocular pressure (IOP) were analyzed before and after the treatment at intervals of 1 week, 1 month, 3 months and 6 months. The measurements were continued in cases of repeated IVTA.
Statistically significant improvements were observed in BCVA in near and distant vision, as well as a decrease in central retinal thickness after all time-intervals following IVTA. BCVA in distant vision was not significantly improved after repeated IVTA. IOP increases were observed 1 week, 1 and 3 months after IVTA, but not at 6 months after IVTA. No sight-threatening side effects of IVTA were observed.
IVTA is useful in stabilizing DME progression, although its therapeutic effect may be timelimited.
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