Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another

A detector for continuous measurement of ultra-cold atoms in real time

We present the first detector capable of recording high-bandwidth real time atom number density measurements of a Bose Einstein condensate. Based on a two-color Mach-Zehnder interferometer, our detector has a response time that is six orders of magnitude faster than current detectors based on CCD cameras while still operating at the shot-noise limit. With this minimally destructive system it may be possible to implement feedback to stabilize a Bose-Einstein condensate or an atom laser.Comment: 3 pages, 3 figures, submitted to optics letter

Sources of nutrition in intertidal sea anemones from the south-western Cape, South Africa

Respiration rates of seven species of intertidal sea anemones from the south-western Cape, South Africa were measured with and without illumination to determine whether zooxanthellae contributed to their nutritional needs. Light had no significant effect on oxygen exchange in any of the species, suggesting that all are azooxanthellate. Diets of anemones from two sites, Wooley’s Pool in False Bay and Blouberg on the Atlantic coast some 20 km north of Cape Town, were examined by gut content analysis. Seven species occurred at Wooley’s Pool, but only one (Bunodactis reynaudi) at Blouberg. At Wooley’s Pool 39.4% of anemones contained food, while at Blouberg only 7.4% did so. A wide spectrum of prey taxa were consumed by the various anemone species, although considerable dietary overlap occurred. Pelecypods, gastropods and isopods were ingested by all the species examined. Pelecypods dominated the diet of B. reynaudi at Blouberg (91% occurrence), but were recorded in only 42% of the same species at Wooley’s Pool. The frequency of occurrence of pelecypods in the guts of the other species ranged from 9% (Anthothoe stimpsoni) to 28% (Actinia equina). Gastropods were the main prey items eaten by Anthopleura michaelseni (67% occurrence), Pseudactinia flagellifera (43%) and Pseudactinia varia (42%), while isopods were the most frequently occurring constituent in the diets of A. stimpsoni (62%) and Bunodosoma capensis (16%). A. equina was the only species for which insects were a regular part of the diet (26% occurrence). Platyhelminths were found only in the guts of B. capensis (11%); holothurians only in B. reynaudi at Wooley’s Pool (2%), and crinoids only in P. flagellifera (2%). Large quantities of algal material and indigestible debris were also ingested, indicating that sea anemones are non-selective feeders. Cluster analysis and multi-dimensional scaling techniques revealed four distinct feeding groups among the anemone assemblages. These are characterized as microphagous (A. stimpsoni), generalist (S. capensis and A. equina), macrophagous (S. reynaudi at Wooley’s Pool, A. michaelseni, P. flagellifera and P. varia) and specialist bivalve- feeder (B. reynaudi at Blouberg)

Digestion rates of prey eaten by intertidal sea anemones from the south-western Cape, South Africa

Digestion rates were determined for natural prey items offered to each of seven species of sea anemones found at Wooley's Pool in False Say and to the single species (Bunodactis reynaudl) recorded at Siouberg on the Atlantic coast of the south-western Cape, South Africa.This was done by examining prey items removed from the coelenterons at regular intervals after feeding and assessing their degree of digestion according to a predetermined scale. There was considerable variation in the gut retention times between different anemone species offered the same prey types, with Actinia equina consistently showing the shortest gut retention times (12 h for amphipods, 15 h for pelecypods and 23 h for isopods). Of the various prey categories tested, amphipods tended to be the most rapidly digested group, while molluscs and echinoderms usually remained in the coelenteron the longest. Mean gut retention times in B. reynaudi, the only species found both in False Bay (1 TC) and on the cold west coast (12'C) were markedly longer (72 vs 60 hand 43 vs 30 h for pelecypods and gastropods respectively) at the lower temperature.S. Afr. J. Zool. 1997,32(4

Sagittal Subtalar and Talocrural Joint Assessment During Ambulation With Controlled Ankle Movement (CAM) Boots

Background: The purpose of the current study was to determine sagittal plane talocrural and subtalar kinematic differences between barefoot and controlled ankle movement (CAM) boot walking. This study used fluoroscopic images to determine talar motion relative to tibia and calcaneal motion relative to talus. Methods: Fourteen male subjects (mean age 24.1 ± 3.5 years) screened for normal gait were tested. A fluoroscopy unit was used to collect images at 200 Hz during stance. Sagittal motion of the talocrural and subtalar joints were analyzed barefoot and within short and tall CAM boots. Results: Barefoot talocrural mean maximum plantar and dorsiflexion were 9.2 ± 5.4 degrees and −7.5 ± 7.4 degrees, respectively; short CAM boot mean maximum plantar and dorsiflexion were 3.2 ± 4.0 degrees and −4.8 ± 10.2 degrees, respectively; and tall CAM boot mean maximum plantar and dorsiflexion were −0.2 ± 3.5 degrees and −2.4 ± 5.1 degrees, respectively. Talocrural mean range of motion (ROM) decreased from barefoot (16.7 ± 5.1 degrees) to short CAM boot (8.0 ± 4.9 degrees) to tall CAM boot (2.2 ± 2.5 degrees). Subtalar mean maximum plantarflexion angles were 5.3 ± 5.6 degrees for barefoot walking, 4.1 ± 5.9 degrees for short CAM boot walking, and 3.0 ± 4.7 degrees for tall CAM boot walking. Mean minimum subtalar plantarflexion angles were 0.7 ± 3.2 degrees for barefoot walking, 0.7 ± 2.9 degrees for short CAM boot walking, and 0.1 ± 4.8 degrees for tall CAM boot walking. Subtalar mean ROM decreased from barefoot (4.6 ± 3.9 degrees) to short CAM boot (3.4 ± 3.8 degrees) to tall CAM boot (2.9 ± 2.6 degrees). Conclusion: Tall and short CAM boot intervention was shown to limit both talocrural and subtalar motion in the sagittal plane during ambulation. The greatest reductions were seen with the tall CAM boot, which limited talocrural motion by 86.8% and subtalar motion by 37.0% compared to barefoot. Short CAM boot intervention reduced talocrural motion by 52.1% and subtalar motion by 26.1% compared to barefoot. Clinical Relevance: Both short and tall CAM boots reduced talocrural and subtalar motion during gait. The short CAM boot was more convenient to use, whereas the tall CAM boot more effectively reduced motion. In treatments requiring greater immobilization of the talocrural and subtalar joints, the tall CAM boot should be considered

Factors deterring and prompting the decision to attempt suicide on the railway networks: findings from 353 online surveys and 34 semi-structured interviews

Background There is a suicide on the British railways every 36 hours. However, the reasons why people choose to die by train are not well understood. Aims To explore factors influencing and discouraging the decision to attempt suicide on the railway networks. Method We conducted an online survey and qualitative interviews with individuals who had contemplated or attempted suicide by train. Results A total of 353 survey responders had considered and 23 had attempted suicide at rail locations (including railways and metro/underground); a third of these cases were impulsive. The most frequently reported motivations for contemplating or attempting suicide were perceptions of quick and certain lethality (54 and 37%, respectively) and easy access to rail settings (33 and 38%, respectively). The main factor discouraging people from rail suicide was its wider impact, especially on train drivers (19%). In qualitative interviews (N = 34) the desire to avoid intervention from others was also a common motivating factor for attempting suicide on the railway networks. Conclusions People attempt suicide by train because railway settings are easy to access and because of an inaccurate perception of certain and quick lethality. Tackling exaggerated perceptions of lethality may help reduce suicides by train