Partial or Complete Unloading of Skeletal Muscle Leads to Specific Alterations of Anabolic Signal Transduction

Consequences of disuse atrophy of skeletal muscle observed during spaceflight on astronaut health and performance are a focal point of space research. Decrements of both muscle mass and protein synthesis rates have been observed with exposure to varying muscle loading environments (1G \u3e partial loading \u3e 0G), and most of the reduced muscle mass can be attributed to diminished rates of synthesis. However, specific mechanisms behind unloading-dependent reductions of protein synthesis are not well defined. PURPOSE: To determine whether or not alterations of anabolic signal transduction was responsible for the changes previously observed in fractional synthesis rates with specific gravitational loading paradigms. METHODS: Female BALB/cByJ were normalized by bodyweight and assigned to normal cage ambulation (1G), partial weight bearing suspension titrated to approximately 33% bodyweight (G/3), partial weight bearing titrated to 16% bodyweight (G/6) and full unloading of hind limbs (0G) in specially designed cages. All mice were subjected to that loading environment for 21d prior to tissue harvest, and monitored daily. Immunoblotting of the gastrocnemius (n=23) was carried out to analyze alterations of anabolic signal transduction. Although numerous signaling intermediates were assessed, the focus of this abstract will be on ribosomal protein S6 kinase (p70-S6K). This important protein has served as a marker of protein synthesis signal transduction as well as the anabolic capacity in skeletal muscle. RESULTS: Regardless of loading paradigm, no differences were detected among groups for the activation of p70-S6K (as indicated by the phospho: total protein content). Total protein content, however, was ~27% lower than control in 0G and G/3 (P=0.008) with G/6 not being different from control (P\u3e0.05). CONCLUSION: In combination with previous data (unpublished observations), Partial gravitational fields at least partially rescues anabolic signaling, suggesting that a threshold level of stimulus is necessary to maintain anabolic capacity in muscle. These results may have important implications towards the development of strategies designed to counter the effects of partial/complete unloading on skeletal muscle based on how the anabolic capacity of muscle is affected

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

The data set development for the National Spinal Cord Injury Registry of Iran (NSCIR-IR): progress toward improving the quality of care

STUDY DESIGN: Descriptive study. OBJECTIVES: The aim of this manuscript is to describe the development process of the data set for the National Spinal Cord Injury Registry of Iran (NSCIR-IR). SETTING: SCI community in Iran. METHODS: The NSCIR-IR data set was developed in 8 months, from March 2015 to October 2015. An expert panel of 14 members was formed. After a review of data sets of similar registries in developed countries, the selection and modification of the basic framework were performed over 16 meetings, based on the objectives and feasibility of the registry. RESULTS: The final version of the data set was composed of 376 data elements including sociodemographic, hospital admission, injury incidence, prehospital procedures, emergency department visit, medical history, vertebral injury, spinal cord injury details, interventions, complications, and discharge data. It also includes 163 components of the International Standards for the Neurologic Classification of Spinal Cord Injury (ISNCSCI) and 65 data elements related to quality of life, pressure ulcers, pain, and spasticity. CONCLUSION: The NSCIR-IR data set was developed in order to meet the quality improvement objectives of the registry. The process was centered around choosing the data elements assessing care provided to individuals in the acute and chronic phases of SCI in hospital settings. The International Spinal Cord Injury Data Set was selected as a basic framework, helped by comparison with data from other countries. Expert panel modifications facilitated the implementation of the registry process with the current clinical workflow in hospitals

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes

The data set development for the National Spinal Cord Injury Registry of Iran (NSCIR-IR): progress toward improving the quality of care

STUDY DESIGN: Descriptive study. OBJECTIVES: The aim of this manuscript is to describe the development process of the data set for the National Spinal Cord Injury Registry of Iran (NSCIR-IR). SETTING: SCI community in Iran. METHODS: The NSCIR-IR data set was developed in 8 months, from March 2015 to October 2015. An expert panel of 14 members was formed. After a review of data sets of similar registries in developed countries, the selection and modification of the basic framework were performed over 16 meetings, based on the objectives and feasibility of the registry. RESULTS: The final version of the data set was composed of 376 data elements including sociodemographic, hospital admission, injury incidence, prehospital procedures, emergency department visit, medical history, vertebral injury, spinal cord injury details, interventions, complications, and discharge data. It also includes 163 components of the International Standards for the Neurologic Classification of Spinal Cord Injury (ISNCSCI) and 65 data elements related to quality of life, pressure ulcers, pain, and spasticity. CONCLUSION: The NSCIR-IR data set was developed in order to meet the quality improvement objectives of the registry. The process was centered around choosing the data elements assessing care provided to individuals in the acute and chronic phases of SCI in hospital settings. The International Spinal Cord Injury Data Set was selected as a basic framework, helped by comparison with data from other countries. Expert panel modifications facilitated the implementation of the registry process with the current clinical workflow in hospitals

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome