Observation of a correlated free four-neutron system.

A long-standing question in nuclear physics is whether chargeless nuclear systems can exist. To our knowledge, only neutron stars represent near-pure neutron systems, where neutrons are squeezed together by the gravitational force to very high densities. The experimental search for isolated multi-neutron systems has been an ongoing quest for several decades1, with a particular focus on the four-neutron system called the tetraneutron, resulting in only a few indications of its existence so far2-4, leaving the tetraneutron an elusive nuclear system for six decades. Here we report on the observation of a resonance-like structure near threshold in the four-neutron system that is consistent with a quasi-bound tetraneutron state existing for a very short time. The measured energy and width of this state provide a key benchmark for our understanding of the nuclear force. The use of an experimental approach based on a knockout reaction at large momentum transfer with a radioactive high-energy 8He beam was key.

OPTN/SRTR 2020 Annual Data Report: Lung.

For the first time in a decade, both the number of candidates added to the waiting list and the number of lung transplants performed decreased from the year prior; the number of lung donors also declined. This slowing of transplant activities in 2020 was associated with a modest increase in waitlist mortality. The year 2020 was notable for the global outbreak of the COVID-19 pandemic, which undoubtedly influenced all trends noted in lung transplantation. Time to transplant continued to decrease, with a median time to transplant of 1.4 months across all waitlist candidates. Posttransplant survival remained stable, with 89.4% of transplant recipients surviving to 1 year, 74.8% to 3 years, and 61.2% to 5 years.

OPTN/SRTR 2019 Annual Data Report: Lung.

The number of lung transplants performed continues to increase annually and reached an all-time high in 2019, with decreasing waitlist mortality. These trends are attributable to an increasing number of candidates listed for transplant each year and a continuing increase in the number of donors. Despite these favorable trends, 6.4% of lungs recovered for transplant were not transplanted in 2019, and strategies to optimize use of these available organs may reduce the number of waitlist even further. Time to transplant continued to decrease, as over 50% of candidates waited 3 months or less in 2019, yet regional heterogeneity remained despite policy changes intended to improve allocation equity. Small gains continued in posttransplant survival, with 1-year survival at 88.8%; 3 year, 74.4%; 5 year, 59.2%, and 10 year, 33.1 %.

OPTN/SRTR 2018 Annual Data Report: Lung.

The primary goal of US lung allocation policy is to ensure that candidates with the highest risk for mortality receive appropriate access to lung transplant. In 2018, 2562 lung transplants were performed in the US, reflecting a 31% increase over the past 5 years. More candidates are being listed for lung transplant, and the number of donors has increased substantially. Despite an increase of 84 lung transplants in 2018, 365 adult candidates died or became too sick to undergo transplant. In 2018, 24 new child (ages 0-11 years) candidates were added to the lung transplant waiting list. Fifteen lung transplants were performed in recipients aged 0-11 years, three in recipients aged younger than 1 year, two in recipients aged 1-5 years, and ten in recipients aged 6-11 years. Of 27 child candidates removed from the waiting list in 2018, 16 (59.3%) were removed due to undergoing transplant, six (22.2%) due to death, one (3.7%) due to improved condition, and one (3.7%) due to becoming too sick to undergo transplant.

OPTN/SRTR 2017 Annual Data Report: Lung.

Each year since 2012, the number of lung transplants has increased, reflecting an increase in the number of donors, improved use of recovered organs, and more candidates being listed for transplant. However, the need for organs continues to outpace available donors. Despite an increase of 126 donors in 2017, 1360 candidates remained on the waiting list at the end of the year, and 326 patients died or became too sick to undergo transplant. Approximately 14,000 individuals were living with a lung transplant in 2017; 9492 were aged 50 years or older, 4075 were aged 18-49 years, and 408 were aged younger than 18 years.

OPTN/SRTR 2016 Annual Data Report: Lung.

In 2016, 2692 candidates aged 12 years or older were added to the lung transplant waiting list; 2345 transplants were performed, the largest number of any prior year. The median waiting time for listed candidates in 2016 was 2.5 months, and waiting times were shortest for group D candidates. The transplant rate increased to 191.9 transplants per 100 waitlist years in 2016, with a slight decrease in waitlist mortality to 15.1 deaths per 100 waitlist years. Short-term survival continued to improve, with a 6-month death rate of 6.6% and a 1-year death rate of 10.8% among recipients in 2015 compared with 8.0% and 13.3%, respectively, among recipients in 2014. Long-term survival rates remained unchanged; 55.6% of recipients were alive at 5 years. In 2016, 23 new candidates aged 0-11 years were added to the waiting list and 16 lung transplants were performed. Incidence of posttransplant mortality for lung transplant recipients aged 0-11 years who underwent transplant in 2014-2015 was 13.8% at 6 months and 19.6% at 1 year. Changes in waitlist and transplant demographic features continued to evolve following implementation of the revised lung allocation score in 2015. Some early trends that may be attributable to the revised LAS are shorter waiting times, stabilization of the number of group D candidates listed for transplant, and convergence of LAS with lower prevalence of extremely high scores.

[Postmenopausal lichen planopilaris also known as fibrosing frontotemporal alopecia Kossard : An evidence-oriented practical guide to treatment from the University of the Saarland, Hair Research Center of the Dr. Rolf M. Schwiete Foundation]. / Postmenopausaler Lichen planopilaris alias fibrosierende frontotemporale Alopezie Kossard : Ein evidenzorientierter "practical guide to treatment" des Haarforschungszentrums der Dr. Rolf M. Schwiete Stiftung an der Universität des Saarlandes.

Postmenopausal lichen planopilaris (PLPP), also known as fibrosing frontotemporal alopecia Kossard (FFAK), is a not uncommon inflammatory scalp disease affecting approximately 5% of patients at specialized hair centers. The overall incidence of sporadic occurrence is believed to be just under 1% in the older, predominantly female, general population. Since the disease is often undiagnosed, it is statistically likely to be underrepresented. It especially occurs in postmenopausal women who are in the 6th and 7th decade of life (90%), but also in about 10% of premenopausal women, and in men it is documented only in isolated cases. The result is a permanent scarring hair loss accentuated at the front hairline with backward movement towards the neck mostly accompanied by a typical loss of the eyebrows. The disease therefore often leads to significant mental distress and social anxiety in those affected. This is the basis for a compelling need to develop evidence-based therapeutic concepts. While numerous retrospective case series have characterized the phenomenology of FFAK very well, to date there are no randomized controlled trials on evidence-based therapy. Here, we present the Homburger Evidence-Oriented Therapy Algorithm, which is oriented along the available case series evidence: It may (1) serve as a therapy guide for practice and (2) can be used as a basis for working out reliable data based on study evidence. The article contains detailed practical information on photo documentation, biopsy and histological processing up to the practical implementation of, for example, intralesional steroid therapy as well as information on selection criteria for suitable systemic therapies.

From the structure of the skin barrier and dermal formulations to in vitro transport models for skin absorption: skin research in the Netherlands and in Germany.

This review presents an overview of German and Dutch research institutions and their studies in the field of skin drug delivery and adjacent topics. In the Netherlands, the involved research groups are mainly localized in Leiden, whereas in Germany the skin research institutions are spread over the whole country. The scientific studies in the Netherlands focus on the in-depth analysis of human skin composition and its individual components as well as on the development and characterization of dermal drug delivery systems ranging from liquid crystalline systems and vesicles up to microneedles with an emphasis on examining the interactions of these drug delivery systems with the human skin in vitro and in vivo. In Germany, the individual areas of research span from in-depth investigations on various drug delivery systems intended for skin application and the development of novel in vitro models for skin absorption testing up to in vivo studies focusing on the biological performance of topically applied actives. Furthermore, sophisticated analytical techniques are applied for the elucidation of skin assembly and transport processes. In addition, experimentally derived data are correlated with advanced computational modelling. Even though the individual research topics in the Netherlands and Germany are quite diverse, the exchange of knowledge and interdisciplinary collaborations between the two neighbouring countries were and are still frequently made. In this context, the review aims at highlighting crosslinks between the different institutions and individual persons to complete the picture. For each institution, the principal investigators and their studies are presented and the upcoming young scientists are introduced as an outlook for the field. This review does not claim completeness, but is rather intended to give a general overview of Dutch and German research in the field of skin drug delivery and adjacent topics.

Infrared densitometry: a fast and non-destructive method for exact stratum corneum depth calculation for in vitro tape-stripping.

The investigation of drug penetration into the stratum corneum (SC) by tape-stripping requires an accurate measure of the amount of SC on each tape-strip in order to determine the depth inside the SC. This study applies infrared densitometry (IR-D) to in vitro tape-stripping using the novel Squame Scan(R) 850A. The device had recently been shown to provide accurate measurements of the SC depth for tape-stripping in vivo. Furthermore, the suitability of IR-D for determining the endpoint of tape-stripping, i.e. complete SC removal, was tested. The SC depth was computed from the IR-D data of sequential tape-strips and compared to the results of a protein assay as gold standard. IR-D provided accurate depth results both for freshly excised skin and for skin stored frozen for up to 3 months. In addition, the lower limit of quantification of IR-D indicates the complete removal of the SC (less than 5% of the total SC remaining) and can be used for adjusting the number of tapes applied in situ. Therefore, IR-D is an accurate, fast and non-destructive method for SC depth determination.

Laser Transit-Time Measurements between the Earth and the Moon with a Transportable System.

A high-radiance, pulsed laser system with a transportable transmitting unit was used at Agassiz Station, Harvard College Observatory, Harvard, Massachusetts, to measure the transit times of 25-nanosecond, 10-joule, 530-nanometer pulses from the earth to the Apollo 15 retroreflector on the moon and back.

PLGA nanoparticles stabilized with cationic surfactant: safety studies and application in oral delivery of paclitaxel to treat chemical-induced breast cancer in rat.

PURPOSE: This study was carried out to formulate poly(lactide-co-glycolide) (PLGA) nanoparticles using a quaternary ammonium salt didodecyl dimethylammonium bromide (DMAB) and checking their utility to deliver paclitaxel by oral route. METHODS: Particles were prepared by emulsion solvent diffusion evaporation method. DMAB and particles stabilized with it were evaluated by MTT and LDH cytotoxicity assays. Paclitaxel was encapsulated in these nanoparticles and evaluated in a chemical carcinogenesis model in Sprague Dawley rats. RESULTS: MTT and LDH assays showed the surfactant to be safe to in vitro cell cultures at concentrations <33 microM. PLGA nanoparticles prepared using this stabilizer were also found to be non-toxic to cell lines for the duration of the study. When administered orally to rats bearing chemically induced breast cancer, nanoparticles were equally effective/better than intravenous paclitaxel in cremophor EL at 50% lower dose. CONCLUSIONS: This study proves the safety and utility of DMAB in stabilizing preformed polymers like PLGA resulting in nanoparticles. This preliminary data provides a proof of concept of enabling oral chemotherapy by efficacy enhancement for paclitaxel.

Biogeographic and phylogenetic diversity of thermoacidophilic cyanidiales in Yellowstone National Park, Japan, and New Zealand.

Members of the rhodophytan order Cyanidiales are unique among phototrophs in their ability to live in extreme environments that combine low pH levels ( approximately 0.2 to 4.0) and moderately high temperatures of 40 to 56 degrees C. These unicellular algae occur in far-flung volcanic areas throughout the earth. Three genera (Cyanidium, Galdieria, and Cyanidioschyzon) are recognized. The phylogenetic diversity of culture isolates of the Cyanidiales from habitats throughout Yellowstone National Park (YNP), three areas in Japan, and seven regions in New Zealand was examined by using the chloroplast RuBisCO large subunit gene (rbcL) and the 18S rRNA gene. Based on the nucleotide sequences of both genes, the YNP isolates fall into two groups, one with high identity to Galdieria sulphuraria (type II) and another that is by far the most common and extensively distributed Yellowstone type (type IA). The latter is a spherical, walled cell that reproduces by internal divisions, with a subsequent release of smaller daughter cells. This type, nevertheless, shows a 99 to 100% identity to Cyanidioschyzon merolae (type IB), which lacks a wall, divides by "fission"-like cytokinesis into two daughter cells, and has less than 5% of the cell volume of type IA. The evolutionary and taxonomic ramifications of this disparity are discussed. Although the 18S rRNA and rbcL genes did not reveal diversity among the numerous isolates of type IA, chloroplast short sequence repeats did show some variation by location within YNP. In contrast, Japanese and New Zealand strains showed considerable diversity when we examined only the sequences of 18S and rbcL genes. Most exhibited identities closer to Galdieria maxima than to other strains, but these identities were commonly as low as 91 to 93%. Some of these Japanese and New Zealand strains probably represent undescribed species that diverged after long-term geographic isolation.

Nortriptyline hydrochloride skin absorption: development of a transdermal patch.

The influence of propylen glycol (PG), ethanol, and oleic acid (OA) on nortriptyline hydrochloride (NTH) penetration through human epidermis was studied in vitro at two different pH values (5.5 and 7.4). The influence of lactic acid and polysorbate 80 was studied for a pH of 5.5. Permeation studies through Heat Separated Epidermis, as well as the enhancing effect of the different vehicles, showed a pH dependency. A pH value of 5.5 in the donor solution decreases significantly the permeability coefficient (Kp) with respect to a pH value of 7.4 (0.011+/-0.004 x 10(-6) versus 0.36+/-0.04 x 10(-6)cm/s). The vehicles showed an increasing enhancement effect in the order: polysorbate 80>ethanol/PG/OA>PG>ethanol>ethanol/lactic acid>lactic acid at pH 5.5 while they reduced the permeation of NTH at pH 7.4. Considering the results obtained at pH 5.5, the maximum enhancement ratios were found for polysorbate 80 and the combination ethanol/PG/OA (10.72 and 3.90). Both vehicles were selected for designing a NTH transdermal delivery system (NTH-TDS) using (hydroxypropyl)methyl-cellulose as polymer. The NTH-TDS based on the combination of ethanol/PG/OA showed an enhancement ratio with respect to control of 2.09 and the addition of polysorbate 80 to the matrix, of 5.82.

Decomposition of the telomere-targeting agent BRACO19 in physiological media results in products with decreased inhibitory potential.

The stability of the acridine-based telomere-targeting agent BRACO19, a G-quadruplex stabilizing substance, was tested at different pH, temperature and in different dissolution media. Analysis was performed by HPLC. Decomposition products were examined by LC/MS and NMR. The TRAP assay was used to determine the inhibitory potential of the decomposition products on telomerase activity. The results show that the stability of BRACO19 strongly depends on pH and temperature. Decomposition was fastest at physiological pH and temperature while the type of dissolution medium had no major influence on stability. The most probable mechanism for this decomposition seems to be a hydrolysis of the amide bonds in position 3 and 6 of the acridine ring and/or a deamination of the phenyl ring. The decomposition products showed a reduced inhibitory potential compared to the parent compound BRACO19. The results demonstrate that the preparation of dosage forms and their storage conditions will have an important influence on the stability--and hence biological efficacy--of BRACO19 and related substances.

Traumatic penile injuries--mechanisms and treatment.

Injuries of the penis are uncommon but represent urological emergencies. We report 3 cases of penile trauma illustrating the diversity of penile injury presentation. Radiological investigations are only mandatory if there is any suspicion of a urethral injury. Primary surgical approach is recommended in cases of penile fracture or local wound infection. An immediate operative exploration with removal of hematoma and primary defect closure should be done in every case. Surgical management should not be delayed to avoid late complications.

Influence of human skin specimens consisting of different skin layers on the result of in vitro permeation experiments.

The literature exhibits high variation in results from drug permeation experiments across human skin. Our purpose was to investigate the influence of human skin specimens, consisting of different skin layers and resulting from different skin preparation techniques, on the in vitro permeation of a model drug, i.e. flufenamic acid (FFA). FFA permeation across human (1) trypsin-isolated stratum corneum, (2) heat-separated epidermis and (3) dermis, (4) dermatomized skin and (5) full-thickness skin (FTS) from either a hydrophilic or lipophilic donor was investigated in Franz-type diffusion cells. Cumulative permeated drug amounts were plotted versus time, and a fit to Fick's 2nd law of diffusion was performed. Since performing skin diffusion experiments in the laboratory is time consuming and expensive, especially when using FTS, we also investigated the possibility of calculating the resistances of composite skin layers from the diffusion resistances of the individual skin layers. Due to short lag time, practical handling and economic preparation, heat-separated epidermis appears to be superior in human skin in vitro permeation experiments compared to separated stratumcorneum sheets, dermatomized skin and FTS. Furthermore, we found a good correlation between calculated and experimental resistances which underlines that calculation of the total diffusion resistance of composed skin preparations from resistances of individual skin layers is legitimate and useful. Considering our findings, improved interpretation of literature data and more consistent results for future permeation experiments are possible.

Embryonic chicken trachea as a new in vitro model for the investigation of mucociliary particle clearance in the airways.

Mucociliary clearance (MC) is an important defense mechanism of the respiratory system to eliminate inhaled and possibly noxious particles from the lung. Although the principal mechanics of MC seem to be relatively clear there are still open questions regarding the long-term clearance of particles. Therefore, we have developed a new set-up based on embryonic chicken trachea (ECT) to investigate mucociliary particle clearance in more detail. ECT was placed in an incubation chamber after carbon particles were applied and tracked using optical microscopy. The aim of the study was to validate this model by investigating the impact of temperature, humidity and drugs on particle transport rates. Particles were transported reproducibly along the trachea and clearance velocity (2.39 +/- 0.25) mm/min was found to be in accordance to data reported in literature. Variation in temperature resulted in significantly reduced MC: (0.40 +/- 0.12) mm/min (20 degrees C); (0.42 +/- 0.10) mm/min (45 degrees C). Decreasing humidity (99-60%) had no significant effect on MC, whereas reduction to 20% humidity showed a significant influence on particle clearance. The use of different cilio- and muco-active drugs (propranolol, terbutalin, N-acetylcysteine) resulted in altered MC according to the pharmacological effect of the substances: a concentration dependent decrease of MC was found for Propranolol. From our results we conclude that this model can be employed to investigate MC of particles in more detail. Hence, the model may help to understand and identify decisive physico-chemical parameters for MC and to answer open questions regarding the long-term clearance phenomenon.

Dexamethasone-loaded nanoparticle-coated microparticles: correlation between in vitro drug release and drug transport across Caco-2 cell monolayers.

This work reports the preparation of dexamethasone in nanoparticle-coated microparticles and the study of the influence of such microencapsulation on drug absorption across Caco-2 cell monolayers. Nanoparticle-coated microparticles were prepared by spray-drying using nanocapsules (NC) or nanospheres (NS) in aqueous suspensions as coating material. Drug contents ranged from 64 to 134mgg(-1), yields between 49% and 67% and moisture content below 2.0%. SEM and AFM analysis demonstrated that the nanoparticle-coated microparticles (20-53microm) show nanostructures on their surface with a similar diameter compared to the aqueous suspensions. The type of nanocoating material had a significant influence on the drug release profile and on the drug permeation across Caco-2 cells: NC-coated microparticles led to a prolonged release and slower transport across Caco-2 cell monolayers, while the NS-coated microparticles showed a faster release and Caco-2 transport compared to uncoated microparticles. The correlation between the amount of drug permeated and the drug released (%) suggests that the drug absorption from such a delivery system is controlled mainly by the release rate rather than by epithelial permeability. Caco-2 transport studies appear to be a useful characterization tool for the development of microparticulate oral controlled release systems.

Development of a fluorescence-based assay for screening of modulators of human organic anion transporter 1B3 (OATP1B3).

The organic anion transporting protein 1B3 (OATP1B3), formerly termed OATP8, is responsible for uptake and subsequent elimination of multiple amphipathic drugs by the liver. In silico methods for the prediction of transport rates for drugs and drug-like molecules might provide an important tool in drug development. Most prediction methods however require a large training set of in vitro experimental data in order to yield reliable results. To obtain these data, we have developed a fluorescence-based assay that allows screening a relatively high number of substances for their transporter affinity. HEK293 cells overexpressing OATP1B3 (HEK-OATP8) [Y. Cui, J. Konig, D. Keppler, Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2, Mol. Pharmacol. 60 (2001) 934-943.] were tested for transport of Fluo-3. Fluo-3 uptake could be seen in a concentration-dependent manner. Uptake can be inhibited completely by the addition of the known OATP1B3-inhibitor rifampicin proving that Fluo-3 is transported by OATP1B3. To verify the suitability of the system to identify modulators of OATP1B3, we tested known substrates for competitively inhibiting the Fluo-3 transport by giving them simultaneously with a 2muM Fluo-3-solution to the cells. The transport of Fluo-3 was decreased by all test substrates in a concentration dependent manner.

The effect of polymer size and charge of molecules on permeation through synovial membrane and accumulation in hyaline articular cartilage.

The treatment of joint related diseases often involves direct intra-articular injections. For rational development of novel delivery systems with extended residence time in the joint, detailed understanding of transport and retention phenomena within the joint is mandatory. This work presents a systematic study on the in vitro permeation, penetration and accumulation of model polymers with differing charges and molecular weights in bovine joint tissue. Permeation experiments with bovine synovial membrane were performed with PEG polymers (6-200 kDa) and methylene blue in customized diffusion chambers. For polyethylene glycol, 2-fold (PEG 6 kDa), 3-fold (PEG 10 kDa) and 13-fold (PEG 35 kDa) retention by the synovial membrane in reference to the small molecule methylene blue was demonstrated. No PEG 200 kDa was found in the acceptor in detectable amounts after 48 h. This showed the potential for a distinct extension of joint residence times by increasing molecular weights. In addition, experiments with bovine cartilage tissue were conducted. The ability for positively charged, high molecular weight chitosans and HEMA-Co-TMAP (HCT) polymers (up to 233 kDa) to distribute throughout the entire cartilage matrix was demonstrated. In contrast, a distribution into cartilage was not observed for neutral PEG polymers (6-200 kDa). Furthermore, the positive charge density of different compounds (chitosan, HEMA-Co-TMAP, methylene blue, MSC C1 (neutral NCE) and MSC D1 (positively charged NCE) was found to correlate with their accumulation in bovine cartilage tissue. In summary, the results offer pre-clinical in vitro data, indicating that the modification of molecular size and charge of a substance has the potential to decelerate its clearance through the synovial membrane and to promote accumulation inside the cartilage matrix.