Quantification of Ophthalmic Changes After Long-Duration Spaceflight, and Subsequent Recovery

A subset of crewmembers are subjected to ophthalmic structure changes due to long-duration spaceflight (>6 months). Crewmembers who experience these changes are described as having Spaceflight Associated Neuro-Ocular Syndrome (SANS). Characteristics of SANS include optic disk edema, cotton wool spots, choroidal folds, refractive error, and posterior globe flattening. SANS remains a major obstacle to deep-space and planetary missions, requiring a better understanding of its etiology. Quantification of ocular, structural changes will improve our understanding of SANS pathophysiology. Methods were developed to quantify 3D optic nerve (ON) and ON sheath (ONS) geometries, ON tortuosity, and posterior globe deformation using MR imaging

After-Sensations and Lingering Pain following Examination in Patients with Fibromyalgia Syndrome.

Fibromyalgia syndrome (FMS) is a chronic widespread pain condition with mixed peripheral and central contributions. Patients display hypersensitivities to a spectrum of stimuli. Patients' blunt pressure pain thresholds are typically reduced, and sometimes (∼15%) gentle brushstroke induces allodynia. However, after-sensations following these stimuli have not, to our knowledge, been reported. We examined the perception of blunt pressure and 'pleasant touch' in FMS. Patients were first interviewed and completed standard psychometric questionnaires. We then measured their sensitivity to blunt pressure and perception of pleasant touch including after-sensations; patients were followed for five days evaluating lingering pain from blunt pressure. We recruited 51 FMS patients and 16 pain-free controls (HC) at a UK Pain Management Centre. Forty-four patients completed the after-sensation protocol. Most patients reported pain after application of less mechanical pressure than HCs; median arm and leg thresholds were 167 kPa and 233 kPa. Eighty-four percent (31/37) of patients reported ongoing pain at the site of pressure application one day after testing, and 49% (18/37) still perceived pain at five days. After-sensations following brushstroke were common in the FMS group, reported by 77% (34/44) compared to 25% (4/16) of HCs; 34% (15/44) patients, but no HCs, perceived these after-sensations as uncomfortable. For FMS patients who experienced after-sensations, brushstroke-pleasantness ratings were reduced, and skin was often an important site of pain. Pain after blunt pressure assessment typically lingers for several days. After-sensations following brushstroke stimulation is a previously unreported FMS phenomenon. They are associated with tactile anhedonia and may identify a clinically distinct subgroup

PHYSIOLOGICAL MONITORING OF FLUID SHIFTS DURING ORTHOSTATIC TILT

BACKGROUND While the etiology of the Spaceflight Associated Neuro-ocular Syndrome (SANS) is currently unknown, headward fluid shifts due to the removal of all gravitational vectors in space is hypothesized to be a major contributing factor. A countermeasure (CM) that can successfully redistribute body fluids similar to the upright position on Earth may thus be important for the prevention of SANS. Our SPACE-CENT Study (Studying the Physiological and Anatomical Effects of Centrifugation and Head-Down Tilt) seeks to investigate the cerebral, ocular and vestibular effects of 60-day exposure to strict 6o head-down tilt bed rest as a spaceflight analog with and without daily centrifugation. METHODS This study is part of the ongoing AGBRESA study at the DLR :envihab facility. As one component of our SPACE-CENT project, near-infrared spectroscopy (NIRS) derived total hemoglobin concentrations ([HbT]) from 4 body locations (head, chest, thigh, and calf) was measured before, during and after the international-standard orthostatic tilt test: tilt from supine to +80o, maintain for 15 min, then increase lower-body negative pressure (LBNP) by +10 mmHg every 3 minutes until subjects exhibit pre-syncope signs via a simultaneous drop in blood pressure and heart rate. RESULTS As of October 2019, the entire protocol has been completed on n=12 subjects (4 females), 5 days before bed rest onset and on R+0 following 60 days of -6o HDT bed rest. Significant shifts in [HbT]—proportional to blood volume—were observed from the head towards the feet during tilt to +80o in all subjects (Figure 1). All subjects had tests terminated sooner on R+0 (462±346 sec) than on BDC-5 (1105±464 sec), although the inter-subject variability was large (range=125-1751 sec). Interestingly, a subset of subjects (n=3) exhibited an initial increase in cerebral [HbT] at the onset of +80o, whereas the remainder showed no change or a decrease in cerebral [HbT] following tilt onset, which was predictive of longer orthostatic trials (t=2.46, p=0.022). All subjects exhibited an accelerating decrease in cerebral [HbT] that preceded test termination by 59±54 sec. CONCLUSIONS This represents preliminary findings from the first campaign of the study (12 of a planned 24 subjects). As such, final conclusions are not yet possible. However, the consistency of findings across subjects suggests that NIRS-based measures of fluid shifts along the body axis—and particularly out of the head—can predict the onset of pre-syncope by up to nearly a minute. Such data could be combined with the simultaneously acquired European Space Agency measurements of blood pressure to improve predictions of orthostatic tolerance

Inhibition of N-Methyl-D-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential

It is widely accepted that overactivation of NMDA receptors, resulting in calcium overload and consequent mitochondrial dysfunction in retinal ganglion neurons, plays a significant role in promoting neurodegenerative disorders such as glaucoma. Calcium has been shown to initiate a transient hyperpolarization of the mitochondrial membrane potential triggering a burst of reactive oxygen species leading to apoptosis. Strategies that enhance cell survival signaling pathways aimed at preventing this adverse hyperpolarization of the mitochondrial membrane potential may provide a novel therapeutic intervention in retinal disease. In the retina, brain-derived neurotrophic factor has been shown to be neuroprotective, and our group previously reported a PSD-95/PDZ-binding cyclic peptide (CN2097) that augments brain-derived neurotrophic factor-induced pro-survival signaling. Here, we examined the neuroprotective properties of CN2097 using an established retinal in vivo NMDA toxicity model. CN2097 completely attenuated NMDA-induced caspase 3-dependent and -independent cell death and PARP-1 activation pathways, blocked necrosis, and fully prevented the loss of long term ganglion cell viability. Although neuroprotection was partially dependent upon CN2097 binding to the PDZ domain of PSD-95, our results show that the polyarginine-rich transport moiety C-R(7), linked to the PDZ-PSD-95-binding cyclic peptide, was sufficient to mediate short and long term protection via a mitochondrial targeting mechanism. C-R(7) localized to mitochondria and was found to reduce mitochondrial respiration, mitochondrial membrane hyperpolarization, and the generation of reactive oxygen species, promoting survival of retinal neurons

Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial

Background Induction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain. Methods (1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity (0-10 Likert scale) recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS. Results(1) 76 patients were randomised (38 per group), with 65 (31 active, 34 sham) included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group (95% CI - 1.0, 0.3; p = 0.30) giving an effect size of 0.19 (Cohen's D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia. Conclusions Results from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663

Three-micron spectra of AGB stars and supergiants in nearby galaxies

The dependence of stellar molecular bands on the metallicity is studied using infrared L-band spectra of AGB stars (both carbon-rich and oxygen-rich) and M-type supergiants in the Large and Small Magellanic Clouds (LMC and SMC) and in the Sagittarius Dwarf Spheroidal Galaxy. The spectra cover SiO bands for oxygen-rich stars, and acetylene (C2H2), CH and HCN bands for carbon-rich AGB stars. The equivalent width of acetylene is found to be high even at low metallicity. The high C2H2 abundance can be explained with a high carbon-to-oxygen (C/O) ratio for lower metallicity carbon stars. In contrast, the HCN equivalent width is low: fewer than half of the extra-galactic carbon stars show the 3.5micron HCN band, and only a few LMC stars show high HCN equivalent width. HCN abundances are limited by both nitrogen and carbon elemental abundances. The amount of synthesized nitrogen depends on the initial mass, and stars with high luminosity (i.e. high initial mass) could have a high HCN abundance. CH bands are found in both the extra-galactic and Galactic carbon stars. None of the oxygen-rich LMC stars show SiO bands, except one possible detection in a low quality spectrum. The limits on the equivalent widths of the SiO bands are below the expectation of up to 30angstrom for LMC metallicity. Several possible explanations are discussed. The observations imply that LMC and SMC carbon stars could reach mass-loss rates as high as their Galactic counterparts, because there are more carbon atoms available and more carbonaceous dust can be formed. On the other hand, the lack of SiO suggests less dust and lower mass-loss rates in low-metallicity oxygen-rich stars. The effect on the ISM dust enrichment is discussed.Comment: accepted for A&

Venous Congestion Countermeasure Study (VCCM)

No abstract availabl

The Spitzer Spectroscopic Survey of S-type Stars

S-type AGB stars are thought to be in the transitional phase between M-type and C-type AGB stars. Because of their peculiar chemical composition, one may expect a strong influence of the stellar C/O ratio on the molecular chemistry and the mineralogy of the circumstellar dust. In this paper, we present a large sample of 87 intrinsic galactic S-type AGB stars, observed at infrared wavelengths with the Spitzer Space Telescope, and supplemented with ground-based optical data. On the one hand, we derive the stellar parameters from the optical spectroscopy and photometry, using a grid of model atmospheres. On the other, we decompose the infrared spectra to quantify the flux-contributions from the different dust species. Finally, we compare the independently determined stellar parameters and dust properties. For the stars without significant dust emission, we detect a strict relation between the presence of SiS absorption in the Spitzer spectra and the C/O ratio of the stellar atmosphere. These absorption bands can thus be used as an additional diagnostic for the C/O ratio. For stars with significant dust emission, we define three groups, based on the relative contribution of certain dust species to the infrared flux. We find a strong link between group-membership and C/O ratio. We show that these groups can be explained by assuming that the dust-condensation can be cut short before silicates are produced, while the remaining free atoms and molecules can then form the observed magnesium sulfides or the carriers of the unidentified 13 and 20 micron features. Finally, we present the detection of emission features attributed to molecules and dust characteristic to C-type stars, such as molecular SiS, hydrocarbons and magnesium sulfide grains. We show that we often detect magnesium sulfides together with molecular SiS and we propose that it is formed by a reaction of SiS molecules with Mg.Comment: Accepted for publication in A&

Research Recommendations Following the Discovery of Pain Sensitizing IgG Autoantibodies in Fibromyalgia Syndrome

BACKGROUND: Fibromyalgia syndrome (FMS) is the most common chronic widespread pain condition in rheumatology. Until recently, no clear pathophysiological mechanism for fibromyalgia had been established, resulting in management challenges. Recent research has indicated that serum IgGs may play a role in FMS. We undertook a research prioritisation exercise to identify the most pertinent research approaches that may lead to clinically implementable outputs. METHODS: Research priority setting was conducted in five phases: situation analysis; design; expert group consultation; interim recommendations; consultation and revision. A dialogue model was used, and an international multi-stakeholder expert group was invited. Clinical, patient, industry, funder, and scientific expertise was represented throughout. Recommendation-consensus was determined via a voluntary closed eSurvey. Reporting guideline for priority setting of health research were employed to support implementation and maximise impact. RESULTS: Arising from the expert group consultation (n = 29 participants), 39 interim recommendations were defined. A response rate of 81.5% was achieved in the consensus survey. Six recommendations were identified as high priority- and 15 as medium level priority. The recommendations range from aspects of fibromyalgia features that should be considered in future autoantibody research, to specific immunological investigations, suggestions for trial design in FMS, and therapeutic interventions that should be assessed in trials. CONCLUSIONS: By applying the principles of strategic priority setting we directed research towards that which is implementable, thereby expediating the benefit to the FMS patient population. These recommendations are intended for patients, international professionals and grant-giving bodies concerned with research into causes and management of patients with fibromyalgia syndrome

Small fibre pathology, small fibre symptoms and pain in fibromyalgia syndrome

A proportion of people with fibromyalgia demonstrate small fibre pathology (SFP). However, it is unclear how SFP directly relates to pain phenomenology. Thirty-three individuals with FMS and ten healthy volunteers underwent assessment of SFP and sensory phenotyping using corneal confocal microscopy, validated questionnaires and quantitative sensory testing (QST). Corneal nerve fibre length was used to stratify participants with fibromyalgia into with SFP [SFP+] and without SFP [SFP-]. SFP was detected in 50% of the fibromyalgia cohort. Current pain score and QST parameters did not differ between SFP+ and SFP-. Mechanical pain sensitivity (MPS) demonstrated a significant gain-of-function in the SFP- cohort compared to healthy-volunteers (p = 0.014, F = 4.806, η2 = 0.22). Further stratification revealed a cohort without structural SFP but with symptoms compatible with small fibre neuropathy symptoms and a significant gain in function in MPS (p = 0.020 Chi-square). Additionally, this cohort reported higher scores for both depression (p = 0.039, H = 8.483, η2 = 0.312) and anxiety (p = 0.022, F = 3.587, η2 = 0.293). This study confirms that SFP is present in a proportion of people with fibromyalgia. We also show that in a proportion of people with fibromyalgia, small fibre neuropathy symptoms are present in the absence of structural SFP. Greater mechanical pain sensitivity, depression and anxiety are seen in these individuals