Nonlinear optical microscopy is a novel tool for the analysis of cutaneous alterations in pseudoxanthoma elasticum

Lasers in Medical Science - Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by...     

Effect of pretreatment with immunomodulating agents on the outcome of lymphocytic choriomeningitis virus infection in athymic (nude) and euthymic mice]

Balb/c (euthymic) and nu/nu (athymic) mice were treated intraperitoneally with TP-4 (a synthetic tetrapeptide, thymopoietin sequence analog, Pharmaceutical Product's Factory Gedeon Richter, Budapest, Hungary) or with Mannozym (0.1% zymosan suspension, Institute for Serobacterological Production and Research, HUMAN, Budapest, Hungary), and were infected intracerebrally with LCM virus. Both of the agents contributed to the development of fatal choriomeningitis, consequently they stimulated the cellular immune response in euthymic mice, but the athymic mice, either treated or not, survived the infection, consequently the agents had no effect on the course of LCM virus infection. The results showed that the cellular immune response stimulating effect by both agents was thymus-dependent. Using these agents immunostimulatory effect can be realized only in the presence of the thymus or the T-dependent lymphoid system, respectively.     

The Mineralization Regulator ANKH Mediates Cellular Efflux of ATP,Not Pyrophosphate

The plasma membrane protein ankylosis homologue (ANKH, mouse ortholog: Ank) prevents pathological mineralization of joints by controlling extracellular levels of the mineralization inhibitor pyrophosphate (PPi). It was long thought that ANKH acts by transporting PPi into the joints. We recently showed that when overproduced in HEK293 cells, ANKH mediates release of large amounts of nucleoside triphosphates (NTPs), predominantly ATP, into the culture medium. ATP is converted extracellularly into PPi and AMP by the ectoenzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We could not rule out, however, that cells also release PPi directly via ANKH. We now addressed the question of whether PPi leaves cells via ANKH using HEK293 cells that completely lack ENPP1. Introduction of ANKH in these ENPP1-deficient HEK293 cells resulted in robust cellular ATP release without the concomitant increase in extracellular PPi found in ENPP1-proficient cells. Ank activity was previously shown to be responsible for about 75% of the PPi found in mouse bones. However, bones of Enpp1^−/− mice contained <2.5% of the PPi found in bones of wild-type mice, showing that Enpp1 activity is also a prerequisite for Ank-dependent PPi incorporation into the mineralized bone matrix in vivo. Hence, ATP release precedes ENPP1-mediated PPi formation. We find that ANKH also provides about 25% of plasma PPi, whereas we have previously shown that 60% to 70% of plasma PPi is derived from the NTPs extruded by the ABC transporter, ABCC6. Both transporters that keep plasma PPi at sufficient levels to prevent pathological calcification therefore do so by extruding NTPs rather than PPi itself. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Targeted O2 delivery by blood substitutes: in vitro arteriolar simulations of first- and second-generation products

The O(2) transport from mixtures of commercially produced hemoglobin-based O(2) carriers (HBOCs) and red blood cells (RBCs) flowing through arteriolar-sized (25-mum) conduits is simulated. A generalized treatment of extraluminal O(2) transport processes is used to reflect variations in physiological conditions, such as increased O(2) consumption. Of the HBOCs considered, polymerized bovine hemoglobin (PolyBvHb, p50=54 mmHg), tetrameric cross-linked human hemoglobin (alphaalphaHb, p50=33 mmHg), and PEGylated human hemoglobin (MP4, p50=5 mmHg), only MP4 does not increase O(2) extraction ratios when compared to RBC suspensions alone. A reduction in arteriolar O(2) extraction is likely to be beneficial for HBOCs by preventing O(2)-induced vasoactivity and maximizing the supply of O(2) available to the capillaries. Results from in vivo HBOC transfusion experiments cannot be predicted by the model, unless PolyBvHb has a significant decrease in extraluminal O(2) transport resistance as compared to MP4. This result is consistent with the literature that shows arteriolar O(2) consumption to increase with intravascular pO(2).     

Optimal pulse-inversion imaging for microsphere contrast agents

Microbubbles are used as contrast agents because they scatter incident ultrasound (US) efficiently. Pulse-inversion imaging makes use of the asymmetrical difference in response of a bubble to an US pulse and its symmetrical opposite to obtain improved contrast. In this theoretical work, the principle of pulse-inversion imaging is expanded upon by finding the optimal pulse shape to maximize the signal from a bubble. Given a limit on driving intensity, a suitable norm of the bubble response is maximized using optimal control theory to identify the proper pulse/antipulse driving protocol for a single bubble. The optimal pulse yields a several-fold increase in the normed response over the best sinusoidal pulse of the same driving intensity. It was found that the optimal driving for a single bubble also maximizes the nonlinear response of the cloud if its mean bubble size is the same as that of the single bubble.     

Dilution of microbicide gels with vaginal fluid and semen simulants: effect on rheological properties and coating flow

Microbicides are agents applied topically to the vagina to prevent HIV transmission. Microbicide products formulated as semi-solid dosage forms or "gels" coat vulnerable tissue to deliver active ingredients. Effective microbicide delivery vehicles must have appropriate rheological properties to ensure appropriate deployment in vivo. Microbicide products become diluted by fluids in the vagina after application; dilution affects vehicle rheological properties and mechanics of vaginal distribution, thus affecting efficacy. To simulate the changes that might occur after application, this study analyzed the effects of small dilutions (10-30%) with vaginal fluid and semen simulants on three semi-solid vaginal formulations: a cellulose lubricant (KY Jelly), a polyacrylic acid moisturizer (Replens), and a carrageenan prototype microbicide (Carraguard). Rheological behavior was characterized using cone-and-plate rheometry. Data were fitted to either the power-law, Carreau, or Herschel-Bulkley model. Rheological parameters from these fits were input to models of coating flow due squeezing, and the simulated area coated output from these models was used to compare the responses of the different formulations to the two diluents for varying degrees of dilution. There were differences in the responses of the three materials to dilution. Even small dilutions altered the rank order of vaginal coating rates compared to the undiluted formulations.     

The dMRP/CG6214 gene of Drosophila is evolutionarily and functionally related to the human multidrug resistance-associated protein family

ATP-binding cassette (ABC) transporters are involved in the transport of substrates across biological membranes and are essential for many cellular processes. Of the fifty-six Drosophila ABC transporter genes only white, brown, scarlet, E23 and Atet have been studied in detail. Phylogenetic analyses identify the Drosophila gene dMRP/CG6214 as an orthologue to the human multidrug-resistance associated proteins MRP1, MRP2, MRP3 and MRP6. To study evolutionarily conserved roles of MRPs we have initiated a characterization of dMRP. In situ hybridization and Northern analysis indicate that dMRP is expressed throughout development and appears to be head enriched in adults. Functional studies indicate that DMRP is capable of transporting a known MRP1 substrate and establishes DMRP as a high capacity ATP-dependent, vanadate-sensitive organic anion transporter.     

Effect of microbial immunomodulators on the course of lymphocytic choriomeningitis virus infection in old mice with physiological thymus involution]

Aged mice with physiological thymus involution were treated intraperitoneally with 0.2 ml of live Newcastle Disease Virus (NDV) containing attenuated NDV vaccine (HA titre: log 2(16)/ml) one day before or with Mannozym (0.1% zymosan suspension) four days and one day before intracerebral inoculation with 100 LD50 dose of LCMV. One dose of M was equal to 40 mg/kg zymosan. Both, NDV vaccine and M pretreatments contributed to the development of fatal lymphocytic choriomeningitis, thus enhanced the cellular immune response to LCMV infection. Present results are compared with earlier results which were attained on young adult suckling mice in similar system with pretreatment with different microbial immunomodulators. Present results reinforced the authors' earlier observations that the direction and degree of immunomodulatory effects can be influenced by the actual conditions, like age, of the immune system.