Proposed mechanism for reduced jugular vein flow in microgravity.

Internal jugular flow is reduced in space compared with supine values, which can be associated with internal jugular vein (IJV) thrombosis. The mechanism is unknown but important to understand to prevent potentially serious vein thromboses on long duration flights. We used a novel, microgravity-focused numerical model of the cranial vascular circulation to develop hypotheses for the reduced flow. This model includes the effects of removing hydrostatic gradients and tissue compressive forces - unique effects of weightlessness. The IJV in the model incorporates sensitivity to transmural pressure across the vein, which can dramatically affect resistance and flow in the vein. The model predicts reduced IJV flow in space. Although tissue weight in the neck is reduced in weightlessness, increasing transmural pressure, this is more than offset by the reduction in venous pressure produced by the loss of hydrostatic gradients and tissue pressures throughout the body. This results in a negative transmural pressure and increased IJV resistance. Unlike the IJV, the walls of the vertebral plexus are rigid; transmural pressure does not affect its resistance and so its flow increases in microgravity. This overall result is supported by spaceflight measurements, showing reduced IJV area inflight compared with supine values preflight. Significantly, this hypothesis suggests that interventions that further decrease internal IJV pressure (such as lower body negative pressure), which are not assisted by other drainage mechanisms (e.g. gravity), might lead to stagnant flow or IJV collapse with reduced flow, which could increase rather than decrease the risk of venous thrombosis.

Urinary Calcium for Tracking Bone Loss and Kidney Stone Risk in Space.

INTRODUCTION: Urinary calcium (Uca) levels in space reflect bone loss and kidney stone risk and could be measured using portable devices. This project evaluated the repeatability of Uca measurements to assess how many repeated measurements would be needed to detect significant urinary calcium elevations in space.METHODS: A total of six subjects collected 24-h urine samples weekly for 8 wk and took 500 mg of oral calcium carbonate and 400 IU of vitamin D daily in week 7 and 8. Uca concentration was analyzed using a calcein-based system. The effect of the intake of calcium and vitamin D on Uca levels and the correlation between first void concentration and 24-h mass were assessed with linear mixed effect models. The reproducibility coefficient (RPC) for Uca was determined using Bland-Altman analysis on pairs of measurements at different time points.RESULTS: Oral supplementation did not significantly affect 24-h mass. First void concentration correlated with 24-h mass. The 24-h mass RPCs were 167.0, 116.8, and 108.1 mg for 1-, 2-, and 3-wk average measurements. First void concentration RPCs were 90.6, 76.6, and 72.8 mg L1. Skylab astronauts 24-h mass increased by 88.9 76.0, 123.5 58.3, 142.2 56.5, and 159.9 83.4 mg after 1, 2, 3, and 4 wk in flight.DISCUSSION: Averaging multiple Uca measurements reduced variability effectively and allowed increases likely to be seen in space to be detected. Consecutive Uca measurements could be tracked over time in space to assess the effectiveness of the countermeasure program. First void concentration could potentially be used rather than 24-h collections.Ren J, Stankovic AS, Knaus DA, Phillips SD, Kynor DB, Buckey JC. Urinary calcium for tracking bone loss and kidney stone risk in space. Aerosp Med Hum Perform. 2020; 91(9):689696.

Microgravity-induced ocular changes are related to body weight.

On Earth, tissue weight generates compressive forces that press on body structures and act on the walls of vessels throughout the body. In microgravity, tissues no longer have weight, and tissue compressive forces are lost, suggesting that individuals who weigh more may show greater effects from microgravity exposure. One unique effect of long-duration microgravity exposure is spaceflight-associated neuroocular syndrome (SANS), which can present with globe flattening, choroidal folds, optic disk edema, and a hyperopic visual shift. To determine whether weight or other anthropometric measures are related to ocular changes in space, we analyzed data from 45 individual long-duration astronauts (mean age 47, 36 male, 9 female, mean mission duration 165 days) who had pre- and postflight measures of disk edema, choroidal folds, and manifest ocular refraction. The mean preflight weights of astronauts who developed new choroidal folds [78.6 kg with no new folds vs. 88.6 kg with new folds ( F = 6.2, P = 0.02)] and disk edema [79.1 kg with no edema vs. 95 kg with edema ( F = 9.6, P = 0.003)] were significantly greater than those who did not. Chest and waist circumferences were also significantly greater in those who developed folds or edema. The odds of developing disk edema or new choroidal folds were 55% in the highest- and 9% in the lowest-weight quartile. In this cohort, no women developed disk edema or choroidal folds, although women also weighed significantly less than men [62.9 vs. 85.2 kg ( F = 53.2, P < 0.0001)]. Preflight body weight and anthropometric factors may predict microgravity-induced ocular changes.

Ocular changes over 60 min in supine and prone postures.

Some astronauts are returning from long-duration spaceflight with structural ocular and visual changes. We investigated both the transient and sustained effects of changes in the direction of the gravity vector acting on the eye using changes in body posture. Intraocular pressure (IOP; measured by Perkins tonometer), ocular geometry (axial length, corneal thickness, and aqueous depth-noncontact biometer), and the choroid (volume and subfoveal thickness optical coherence tomography) were measured in 10 subjects (5 males and 5 females). Measures were taken over the course of 60 min and analyzed with repeated-measures analysis of covariance to assess the effects of posture and time. In the supine position, choroidal volume increased significantly with time (average value at <5 min = 8.8 ± 2.3 mm3, 60 min = 9.0 ± 2.4 mm3, P = 0.03). In the prone position, IOP and axial length increased with time (IOP at <5 min 15 ± 2.7 mmHg, 60 min = 19.8 ± 4.1 mmHg, P < 0.0001; axial length at <5 min = 24.29 ± 0.77 mm, 60 min = 24.31 ± 0.76 mm, P = 0.002). Each increased exponentially, with time constants of 5.3 and 14 min, respectively. Prone corneal thickness also increased with time (<5 min = 528 ± 35 µm, 60 min = 537 ± 35 µm3, P < 0.001). Aqueous depth was shortened in the prone position (baseline = 3.22 ± 0.31 mm, 60 min = 3.18 ± 0.32 mm, P < 0.0001) but did not change with time. The data show that changes in the gravity vector have pronounced transient and sustained effects on the geometry and physiology of the eye.NEW & NOTEWORTHY We show that gravity has pronounced transient and sustained effects on the eye by making detailed ocular measurements over 60 min in the supine and prone postures. These data inform our understanding of how gravitational forces can affect ocular structures, which is essential for hypothesizing how ocular changes could occur with microgravity exposure.

Acute effects of changes to the gravitational vector on the eye.

Intraocular pressure (IOP) initially increases when an individual enters microgravity compared with baseline values when an individual is in a seated position. This has been attributed to a headward fluid shift that increases venous pressures in the head. The change in IOP exceeds changes measured immediately after moving from seated to supine postures on Earth, when a similar fluid shift is produced. Furthermore, central venous and cerebrospinal fluid pressures are at or below supine position levels when measured initially upon entering microgravity, unlike when moving from seated to supine postures on Earth, when these pressures increase. To investigate the effects of altering gravitational forces on the eye, we made ocular measurements on 24 subjects (13 men, 11 women) in the seated, supine, and prone positions in the laboratory, and upon entering microgravity during parabolic flight. IOP in microgravity (16.3 ± 2.7 mmHg) was significantly elevated above values in the seated (11.5 ± 2.0 mmHg) and supine (13.7 ± 3.0 mmHg) positions, and was significantly less than pressure in the prone position (20.3 ± 2.6 mmHg). In all measurements,P< 0.001. Choroidal area was significantly increased in subjects in a microgravity environment (P< 0.007) compared with values from subjects in seated (increase of 0.09 ± 0.1 mm(2)) and supine (increase of 0.06 ± 0.09 mm(2)) positions. IOP results are consistent with the hypothesis that hydrostatic gradients affect IOP, and may explain how IOP can increase beyond supine values in microgravity when central venous and intracranial pressure do not. Understanding gravitational effects on the eye may help develop hypotheses for how microgravity-induced visual changes develop.

New phosphine-diamine and phosphine-amino-alcohol tridentate ligands for ruthenium catalysed enantioselective hydrogenation of ketones and a concise lactone synthesis enabled by asymmetric reduction of cyano-ketones.

Enantioselective hydrogenation of ketones is a key reaction in organic chemistry. In the past, we have attempted to deal with some unsolved challenges in this arena by introducing chiral tridentate phosphine-diamine/Ru catalysts. New catalysts and new applications are presented here, including the synthesis of phosphine-amino-alcohol P,N,OH ligands derived from (R,S)-1-amino-2-indanol, (S,S)-1-amino-2-indanol and a new chiral P,N,N ligand derived from (R,R)-1,2-diphenylethylenediamine. Ruthenium pre-catalysts of type [RuCl2(L)(DMSO)] were isolated and then examined in the hydrogenation of ketones. While the new P,N,OH ligand based catalysts are poor, the new P,N,N system gives up to 98% e.e. on substrates that do not react at all with most catalysts. A preliminary attempt at realising a new delta lactone synthesis by organocatalytic Michael addition between acetophenone and acrylonitrile, followed by asymmetric hydrogenation of the nitrile functionalised ketone is challenging in part due to the Michael addition chemistry, but also since Noyori pressure hydrogenation catalysts gave massively reduced reactivity relative to their performance for other acetophenone derivatives. The Ru phosphine-diamine system allowed quantitative conversion and around 50% e.e. The product can be converted into a delta lactone by treatment with KOH with complete retention of enantiomeric excess. This approach potentially offers access to this class of chiral molecules in three steps from the extremely cheap building blocks acrylonitrile and methyl-ketones; we encourage researchers to improve on our efforts in this potentially useful but currently flawed process.

A combined spectroscopic and crystallographic approach to probing drug-human serum albumin interactions.

The displacement of probes that bind selectively to subdomains IIA or IIIA on human serum albumin (HSA) by competing compounds has been followed using fluorescence spectroscopy, and has therefore been used to assign a primary binding site for these compounds in the presence and absence of fatty acids. The crystal structures have also been solved for three compounds: a matched pair of carboxylic acids whose binding strength to HSA unexpectedly decreased as the lipophilicity increased; and a highly bound sulphonamide that appeared not to displace the probes in the displacement assay. The crystallography results support the findings from the fluorescence displacement assay. The results indicate that drug binding to subdomain IB might also be important location for certain compounds.

Enantioselective hydrogenation and transfer hydrogenation of bulky ketones catalysed by a ruthenium complex of a chiral tridentate ligand.

A study on the enantioselective hydrogenation of tertiary alkyl ketones catalysed by a novel class of tridentate-Ru complex is reported. In contrast to the extensively studied [RuCl(2)(diphos)(di-primary amine)] complexes, this new class of hydrogenation catalyst smoothly reduces these less reactive bulky ketones with up to 94 % ee. The same catalyst system can also selectively reduce other potentially problematic substrates such as bulky heterocyclic ketones. Unusually for a pressure hydrogenation catalyst, similar enantioselectivity can be obtained under transfer hydrogenation conditions. The transfer hydrogenations are somewhat slower than the pressure hydrogenations, but this drawback is readily overcome, since we have discovered that a microwave accelerated transfer hydrogenation of the above ketones occurs within 20 min at about 90 degrees C with similar selectivity to that obtained in the pressure hydrogenation system.

Nonselective nonsteroidal antiinflammatory drugs and cardiovascular risk: are they safe?

OBJECTIVE: To assess possible cardiovascular risks associated with use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs). DATA SOURCES: MEDLINE and EMBASE were searched from January 1985 through April 2007 and relevant studies were retrieved. STUDY SELECTION AND DATA EXTRACTION: Peer-reviewed, prospective, double-blind, case-control, and cohort-design studies published in the English language literature were considered eligible for review. Previous meta-analyses and systematic reviews were also analyzed. In total, 17 case-control studies; 9 cohort studies; 1 prospective, double-blind study; 3 meta-analyses; and 1 systematic review of observational studies were identified. DATA SYNTHESIS: Three studies were prospective and the remainder consisted of observational, retrospective studies, with most reporting acute fatal or nonfatal myocardial infarction as the cardiovascular endpoint. Among the nonselective NSAIDs, diclofenac appears to pose the highest risk for cardiovascular toxicity; other agents trend toward a neutral effect with respect to cardiovascular risk. Although the data are suggestive, it remains unclear whether naproxen provides protective cardiovascular effects among patients on chronic therapy. CONCLUSIONS: Currently available data are insufficient for defining evidence-based clinical guidelines for the use of NSAIDs, and the need for additional research, specifically randomized controlled trials, is evident. Diclofenac demonstrates a significant risk while naproxen appears to pose the lowest, albeit nonsignificant, risk for cardiovascular morbidity. Although the current clinical evidence may not warrant recommending naproxen as the preferred NSAID treatment, it may be prudent to avoid diclofenac for patients with cardiovascular risk factors requiring NSAID treatment.

Hepatorenal solvent toxicology.

The liver and kidneys are tissues with a rich blood supply. Thus, with significant exposures, these tissues may be at risk for anatomic or pathophysiologic alterations. It is important to understand the gross, microscopic, and functional anatomy of these important organs to analyze potential adverse effects of solvents.

Dripping-jetting transitions in a dripping faucet.

Fascinating dynamics is known to result when the flow rate Q at which water drips from a faucet varies. Starting with simple (period-1) dripping, the system transitions as Q increases to complex dripping, where it exhibits period-n (n=2,4, em leader ) and chaotic responses, and then jets once Q exceeds a threshold. New experiments and simulations show that high viscosity (micro) liquids, e.g., syrup, transition directly from simple dripping to jetting as Q increases. Phase diagrams showing transitions between simple and complex dripping and jetting in (Q,micro) space are developed. Values of Q for transition from dripping to jetting are estimated from scaling arguments and shown to accord well with simulations.

Biologic markers of exposure to chlorinated solvents.

This article presents the current knowledge and clinical applications of the use of biomarkers of exposure to the halogenated solvents 1,1,1 trichloroethane (methylchloroform), trichloroethylene, tetrachloroethylene (perchloroethylene), and 1,1 dichloroethylene (vinylidene chloride). Although some studies have shown that protein and DNA adducts may form with chlorinated hydrocarbons, their application has not been validated sufficiently to justify their use as biologic markers of exposure.

Solvents and vapor intrusion pathways.

Vapor intrusion must be recognized appropriately as a separate pathway of contamination. Although many issues resemble those of other forms of contamination (particularly its entryway, which is similar to that of radon seepage), vapor intrusion stands apart as a unique risk requiring case-specific action. This article addresses these issues and the current understanding of the most appropriate and successful remedial actions.