Accelerating space radiation countermeasure development through drug repurposing.

The discovery of safe and effective radiation countermeasures (MCM) for long-duration spaceflight is challenging due to the complexity of the space radiation biology and high safety requirements. There are few if any clinically-validated molecular targets for this use case, and preclinical models have several known limitations. These challenges make the evaluation of existing FDA-approved drugs for this indication, or drug repurposing, an attractive strategy to accelerate space radiation countermeasure development. Drug repurposing offers several advantages over de novo drug discovery including established manufacturing methods, human clinical safety data, and well-understood dosing and pharmacokinetic considerations. There are limitations working with a fixed set of possible candidate compounds, but some properties of repurposed drugs can be tailored for well-defined new indications through reformulation and development of drug combinations. Drug repurposing is thus an attractive strategy for mitigating the high risks and costs of drug development and delivering new countermeasures to protect human from space radiation in long-term missions.

Associations of hemoglobin and change in hemoglobin with risk of incident hip fracture in older men and women: the cardiovascular health study.

In a multi-site longitudinal cohort study, decreasing hemoglobin was associated with increased hip fracture risk in men. Anemia was associated with hip fracture in men and in African American women. Decreasing hemoglobin may be a marker of progressing bone fragility, making its serial measurement useful for fracture risk stratification. INTRODUCTION: Hematopoiesis and bone health are interdependent. Anemia has been associated with risk of fracture in humans. To further elucidate this relationship, we hypothesized that decreasing hemoglobin could indicate defective hematopoiesis and would also predict fracture risk. METHODS: We performed a prospective analysis from study baseline (1992) of the Cardiovascular Health Study, a multi-site longitudinal cohort study. A total of 4670 men and women, ages >65 years, who were able to consent and not institutionalized or wheelchair bound, had hemoglobin (Hb) measured in 1992. For 4006 subjects, Hb change from 1989 to 1992 was annualized and divided into sex-specific quartiles. Incident hip fractures were verified against Medicare claims data during a median follow-up of 11.8 years. RESULTS: Nested Cox proportional-hazard models estimated association of hip fracture with anemia (men Hb <13 g/dL, women Hb <12 g/dL) and separately, greatest Hb decrease (versus others). Anemia was associated with increased hip fracture risk in all men (HR 1.59; 95% CI 1.01-2.50) and African American women (HR 3.21; 95% CI 1.07-9.63). In men, an annualized Hb loss of >0.36 g/dL/year was associated with a higher risk of hip fracture (HR 1.67; 95% CI 1.10-2.54), which was lessened by anemia at the start of fracture follow-up (HR 1.53; 95% CI 0.99-2.39). CONCLUSIONS: Decreasing Hb may be an early marker for subsequent hip fracture risk in men, which may be less informative once an anemia threshold is crossed. Only African American women with anemia had increased hip fracture risk, suggesting a race difference in this relationship.

Inductively coupled 30 T magnetic field platform for magnetized high-energy-density plasma studies.

A pulsed high magnetic field device based on the inductively coupled coil concept [D. H. Barnak et al., Rev. Sci. Instrum. 89, 033501 (2018)] is described. The device can be used for studying magnetized high-energy-density plasma and is capable of producing a pulsed magnetic field of 30 T inside a single-turn coil with an inner diameter of 6.5 mm and a length of 6.3 mm. The magnetic field is created by discharging a high-voltage capacitor through a multi-turn solenoid, which is inductively coupled to a small single-turn coil. The solenoid electric current pulse of tens of kA and a duration of several µs is inductively transformed to hundreds of kA in the single-turn coil, thus enabling a high magnetic field. Unlike directly driven single-turn systems that require a high-current and low-inductive power supply, the inductively coupled system operates using a relatively low-current power supply with very relaxed requirements for its inductance. This arrangement significantly simplifies the design of the power supply and also makes it possible to place the power supply at a significant distance from the coil. In addition, the device is designed to contain possible wire debris, which makes it attractive for debris-sensitive applications.

Increasing the magnetic-field capability of the magneto-inertial fusion electrical discharge system using an inductively coupled coil.

Magnetized high energy density physics (HEDP) is a very active and relatively unexplored field that has applications in inertial confinement fusion, astrophysical plasma science, and basic plasma physics. A self-contained device, the Magneto-Inertial Fusion Electrical Discharge System, MIFEDS [G. Fiksel et al., Rev. Sci. Instrum. 86, 016105 (2015)], was developed at the Laboratory for Laser Energetics to conduct magnetized HEDP experiments on both the OMEGA [T. R. Boehly et al., Opt. Commun. 133, 495-506 (1997)] and OMEGA EP [J. H. Kelly et al., J. Phys. IV France 133, 75 (2006) and L. J. Waxer et al., Opt. Photonics News 16, 30 (2005)] laser systems. Extremely high magnetic fields are a necessity for magnetized HEDP, and the need for stronger magnetic fields continues to drive the redevelopment of the MIFEDS device. It is proposed in this paper that a magnetic coil that is inductively coupled rather than directly connecting to the MIFEDS device can increase the overall strength of the magnetic field for HEDP experiments by increasing the efficiency of energy transfer while decreasing the effective magnetized volume. A brief explanation of the energy delivery of the MIFEDS device illustrates the benefit of inductive coupling and is compared to that of direct connection for varying coil size and geometry. A prototype was then constructed to demonstrate a 7-fold increase in energy delivery using inductive coupling.

Prevalence and risk of fracture diagnoses in women across the adult life span: a national cross-sectional study.

In a national sample of women veterans, the rate of lower limb fracture diagnosis was the highest across ages 18-74 years; rates of fracture diagnosis of other skeletal sites peaked in women aged 75+. Women with two or more primary care visits or mental healthcare visits had elevated odds of fracture diagnosis. INTRODUCTION: We assessed the prevalence and healthcare utilization characteristics associated with a diagnosis of any fracture in women of all adult ages within the Veterans Health Administration. METHODS: In 344,488 women during fiscal year 2012, logistic regression models for fracture diagnosis included age, race/ethnicity, residence, number of primary care visits, number of mental healthcare visits, and degree of service-connected disability. RESULTS: Lower limb fracture diagnosis was most prevalent across ages 18-74 years and peaked in women aged 55-64 years. In women aged 75+, the prevalence rates of fracture diagnosis at the hip (102, 95 % CI = 88-115 per 10,000 women), upper limb (100, 95 % CI = 87-114 per 10,000 women), and lower limb (84, 95 % CI = 72-97 per 10,000 women) were the highest. Fractures at other skeletal sites peaked in those aged 75+ years. Black women had the lowest odds of a fracture diagnosis, followed by Asian/Pacific Islander and Hispanic women compared to non-Hispanic White (by 25-51 %, P < 0.05). Having two or more primary care visits or any mental health visit was each associated with an increased risk. Women with five or more primary care visits had a 3.36-fold (95 % CI = 3.02-3.75) greater odds than those with no such visit, and separately, women with five or more mental health visits had a 1.51-fold (95 % CI = 1.43-1.60) greater odds. Women with a fracture diagnosis had higher overall healthcare costs than those without (P < 0.001). CONCLUSIONS: Prevalence of fracture diagnosis differed by age, race/ethnicity, and skeletal site of fracture. Fracture diagnosis may identify women veterans with greater overall healthcare needs.

The potential of mesenchymal stem cells in the management of radiation enteropathy.

Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies.

Note: Experimental platform for magnetized high-energy-density plasma studies at the omega laser facility.

An upgrade of the pulsed magnetic field generator magneto-inertial fusion electrical discharge system [O. Gotchev et al., Rev. Sci. Instrum. 80, 043504 (2009)] is described. The device is used to study magnetized high-energy-density plasma and is capable of producing a pulsed magnetic field of tens of tesla in a volume of a few cubic centimeters. The magnetic field is created by discharging a high-voltage capacitor through a small wire-wound coil. The coil current pulse has a duration of about 1 µs and a peak value of 40 kA. Compared to the original, the updated version has a larger energy storage and improved switching system. In addition, magnetic coils are fabricated using 3-D printing technology which allows for a greater variety of the magnetic field topology.

Association between PDCD1, CTLA4, and MECP2 gene polymorphisms and systemic lupus erythematosus in the Chinese Northern Han.

Systemic lupus erythematosus (SLE) is an autoimmune disease that results in chronic inflammation of different organ systems. Several susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes has yet to be determined. The programmed cell death 1 gene (PDCD1), the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene, and the methyl-CpG-binding protein 2 gene (MECP2) are considered to be the candidate genes associated with SLE. We analyzed the role of PDCD1, CTLA4, and MECP2 gene polymorphisms in Han patients suffering from SLE. Using a case-control study, 263 SLE patients and 263 healthy controls were collected from Chinese Northern Han people. Genomic DNA was prepared from peripheral blood leukocytes and the genotyping was performed using a polymerase chain reaction/ligase detection reaction assay. A statistically significant difference was observed in the rs2239464 and rs2075596 polymorphisms of MECP2 between SLE subjects and controls. The GG genotype in rs2239464 and the GG genotype in rs2075596 might protect against SLE. In contrast, no such association was found in the CTLA4 or PDCD1 polymorphisms. The rs2239464 and rs2075596 polymorphisms of MECP2 might play a significant role in the development of SLE in the Northern Han of China.

Association of regulator of G protein signaling (RGS5) gene variants and essential hypertension in Mongolian and Han populations.

Genetic variants of the RGS5 gene are believed to be risk factors for hypertension and cardiovascular diseases. In this study, we investigated the association between RGS5 gene variants and hypertension in the Mongolian and Han populations. Peripheral blood was obtained from 429 unrelated Mongolian herdsmen and 416 Han farmers [including essential hypertension (EH) patients and controls]. Nine tagSNPs within the RGS5 genes were retrieved from HapMap, and the samples were individually genotyped using the polymerase chain reaction/ligase detection reaction assay. The distribution of the allele frequency of rs12035879 differed significantly between hypertensive subjects and controls in the Han population, while the distribution of the allele and genotype frequencies of rs16849802 differed significantly between hypertensive subjects and controls in the Mongolian population. We observed an association between rs16849802 and EH in the Mongolian population. The frequency of haplotype GAA was significantly higher in the EH group than in controls in the Mongolian population. However, the EH group and controls did not differ significantly in all 6 haplotypes in the Han population. The rs16849802 and haplotype GAA independently increased the risk of EH in Mongolian patients, and may be used as a risk factor for the prediction of high blood pressure.

Association of NPRA and NPRC gene variants and hypertension in Mongolian population.

NPRA and NPRC are candidate susceptibility genes for essential hypertension (EH) and play a key role in the regulation of plasma levels and biological effects of natriuretic peptides. The aims of the present study were to find new genetic markers in the NPRA and NPRC genes and to assess relationships between variants and EH. A total of 797 unrelated Mongolian herdsmen were enrolled, including 389 EH patients and 408 normotensive controls. Genotyping was performed using the polymerase chain reaction/ligase detection reaction assay. The distribution of the T-allele frequency of rs1847018 in NPRC differed significantly between hypertensive subjects and controls. There was an association between rs1847018 and EH in the additive model in NPRC (P < 0.05). There were no significant differences in the genotype and allele frequency distributions for any of the 3 single nucleotide polymorphisms in NPRA between EH and normotensive individuals. In NPRA, the frequency of haplotype TCA in the EH group was significantly lower than in controls, while the frequency of haplotype TCG was significantly higher in the EH group than in controls; Individuals who possessed the TCA haplotype had a significantly lower risk of EH, whereas the presence of haplotype TCG was significantly associated with a higher risk of EH. However, there was no significant difference between the EH group and controls in any of the 8 haplotypes in NPRC. Rs1847018 is a genetic marker of EH in NPRC, and the frequency of haplotype TCA and TCG in NPRA is associated with EH in the Mongolian population.

Association of SNPs in the PPARγ gene and hypertension in a Mongolian population.

The association of single nucleotide polymorphisms (SNPs) in PPARγ with hypertension is controversial. The aim of the present study was to clarify the contributions of PPARγ genetic variants to hypertension through an association study. A total of 414 unrelated Mongolian herdsmen and 524 Han farmers were included in this study. Fourteen intronic SNPs were analyzed and genotyped using a polymerase chain reaction/ligase detection reaction assay. Prior to correction for multiple testing, the SNPs rs6802898 and rs12633551 were significantly associated with the prevalence of hypertension in the Han and Mongolian populations, respectively. The genetic association of each SNP with hypertension was individually tested using logistic regression. The SNP rs6802898 was associated with hypertension in both dominant (P = 0.033) and additive models (P = 0.026) in the Han population, whereas the SNP rs12633551 was associated with hypertension in both dominant (P = 0.014) and additive models (P = 0.0073) in the Mongolian population. Moreover, SNP rs12633551 had a significant effect on systolic and diastolic blood pressure response. However, none of these associations were statistically significant after Bonferroni correction for multiple testing, although there was a significant difference among the haplotypes in the Han and Mongolian populations. Interestingly, there was an association of the PPARγ haplotypes with hypertension even after Bonferroni correction. Thus, determination of the PPARγ haplotypes in different populations may prove informative for assessment of the genetic risk for hypertension.

Vesico-cutaneous fistula: a simple method for continent urinary diversion.

INTRODUCTION: Patients with lower urinary tract anomalies or neurogenic disorders often suffer from voiding difficulties. Clean intermittent catheterization (CIC) is effective for bladder drainage; however, this is often painful. Transurethral catheterization is also impossible in patients with urethral stricture. A Mitrofanoff conduit may solve some of these problems, but a few disadvantages have been reported, including: difficult surgical techniques and frequent operative complications. A vesicostomy is easy to perform but persistent urine leak over the abdomen and diaper rash can be annoying. A better way to achieve continent urinary diversion is indicated. METHOD: Between December 01 1998 and December 31 2013, six patients underwent a vesico-cutaneous fistula for CIC. The etiologies included urethral stricture (n=2) and neurogenic bladder (n=4). The fistula was created at the bladder dome with only the muscle layer of the bladder sutured to the skin. A Foley catheter was left in place for at least two weeks to prevent stoma stricture. After removing the Foley catheter, regular CIC from the fistula was performed every 2 h during the daytime with a Fr. 10-12 feeding tube, depending on the patient's age. Further stenting during the night in the first six months was necessary to prevent early closure of the fistula. Patients were followed with periodic renal ultrasonography, blood tests and urinalysis in the outpatient department. RESULTS: Follow-up ranged from 6 months to 16 years. All patients showed improvements in hydronephrosis. Decreased UTI frequency was seen in five patients. Renal function was normal in five patients, whilst the other suffered from chronic renal failure preoperatively. Only one patient had occasional mild urine leakage from the stoma at night, which was once in two weeks. No patient experienced painful or difficult catheterization and CIC becomes easy, even by young children. CONCLUSIONS: The vesico-cutaneous fistula is a simple, effective and tolerable method for CIC. It may be a substitute for or a transition to a Mitrofanoff conduit in some patients.

Magnetic reconnection between colliding magnetized laser-produced plasma plumes.

Observations of magnetic reconnection between colliding plumes of magnetized laser-produced plasma are presented. Two counterpropagating plasma flows are created by irradiating oppositely placed plastic (CH) targets with 1.8-kJ, 2-ns laser beams on the Omega EP Laser System. The interaction region between the plumes is prefilled with a low-density background plasma and magnetized by an externally applied magnetic field, imposed perpendicular to the plasma flow, and initialized with an X-type null point geometry with B=0 at the midplane and B=8 T at the targets. The counterflowing plumes sweep up and compress the background plasma and the magnetic field into a pair of magnetized ribbons, which collide, stagnate, and reconnect at the midplane, allowing the first detailed observations of a stretched current sheet in laser-driven reconnection experiments. The dynamics of current sheet formation are in good agreement with first-principles particle-in-cell simulations that model the experiments.

Outcomes after surgery in patients with previous stroke.

BACKGROUND: Limited information is available on the association between a medical history of stroke and postoperative outcomes. This study investigated the outcomes following non-neurological surgery in patients with previous stroke. METHODS: Using Taiwan's National Health Insurance Research Database, a nationwide cohort study was conducted of patients who underwent non-neurological surgery between 2008 and 2010 with a medical history of stroke in the 24-month period before operation. Patients who had non-neurological surgeries without previous stroke were selected as controls by the propensity score-matched pair method. Thirty-day postoperative complications and in-hospital mortality were compared between the two groups. RESULTS: Some 1 426 795 adults underwent major inpatient non-neurological surgery, of whom 45 420 had a medical history of previous stroke. Patients with previous stroke who underwent surgery had an increased risk of postoperative pneumonia, septicaemia, acute renal failure, acute myocardial infarction, pulmonary embolism and 30-day in-hospital mortality (adjusted rate ratio (RR) 1·79, 95 per cent c.i. 1·61 to 1·99). Compared with controls, patients with previous stroke due to intracerebral haemorrhage (RR 3·41, 2·97 to 3·91), and those who were treated in intensive care (RR 2·55, 2·24 to 2·90) or underwent neurosurgery (RR 2·49, 2·12 to 2·92), had an increased 30-day in-hospital mortality rate. Postoperative mortality also increased with stroke-related co-morbidities, and with stroke 1-6 months before surgery (RR 3·31, 2·91 to 3·75). CONCLUSION: Patients with previous stroke had a higher risk of adverse postoperative outcomes; their 30-day in-hospital mortality rate was nearly twice that of patients without previous stroke.

HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis.

HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.

Filamentation instability of counterstreaming laser-driven plasmas.

Filamentation due to the growth of a Weibel-type instability was observed in the interaction of a pair of counterstreaming, ablatively driven plasma flows, in a supersonic, collisionless regime relevant to astrophysical collisionless shocks. The flows were created by irradiating a pair of opposing plastic (CH) foils with 1.8 kJ, 2-ns laser pulses on the OMEGA EP Laser System. Ultrafast laser-driven proton radiography was used to image the Weibel-generated electromagnetic fields. The experimental observations are in good agreement with the analytical theory of the Weibel instability and with particle-in-cell simulations.

Saturation of the two-plasmon decay instability in long-scale-length plasmas relevant to direct-drive inertial confinement fusion.

Measurements of the hot-electron generation by the two-plasmon-decay instability are made in plasmas relevant to direct-drive inertial confinement fusion. Density-scale lengths of 400 µm at n(cr)/4 in planar CH targets allowed the two-plasmon-decay instability to be driven to saturation for vacuum intensities above ~3.5×10(14) W cm(-2). In the saturated regime, ~1% of the laser energy is converted to hot electrons. The hot-electron temperature is measured to increase rapidly from 25 to 90 keV as the laser beam intensity is increased from 2 to 7×10(14) W cm(-2). This increase in the hot-electron temperature is compared with predictions from nonlinear Zakharov models.

Fusion yield enhancement in magnetized laser-driven implosions.

Enhancement of the ion temperature and fusion yield has been observed in magnetized laser-driven inertial confinement fusion implosions on the OMEGA Laser Facility. A spherical CH target with a 10 atm D2 gas fill was imploded in a polar-drive configuration. A magnetic field of 80 kG was embedded in the target and was subsequently trapped and compressed by the imploding conductive plasma. As a result of the hot-spot magnetization, the electron radial heat losses were suppressed and the observed ion temperature and neutron yield were enhanced by 15% and 30%, respectively.

Association of TSC gene variants and hypertension in Mongolian and Han populations.

We investigated a possible association between genetic variations in the thiazide-sensitive Na-Cl cotransporter (TSC) gene and essential hypertension (EH) in the Mongolian and Han ethnic groups in Inner Mongolia. Our study included 385 unrelated Mongolian herdsmen and 523 Han farmers. Nine tagSNPs of TSC were identified from the Chinese HapMap database based on pairwise r(2) ≥ 0.5 and minor allele frequency ≥0.05. Genotyping was performed using the PCR/ligase detection reaction assay. Association between tagSNPs and hypertension was investigated under the additive model. There were significant differences between the genotype and allele frequencies of rs13306673 between the EH group and the control group in the Han population. Significant associations were found between the rs7204044 variant and EH in both the Mongolian and Han ethnic groups. The frequency of haplotype GCA in the EH group was significantly higher than in the control group in the Mongolian population. In the Han population, the frequency of haplotype TGG was significantly higher in the EH group than in controls, whereas haplotype TGA occurred significantly less often in EH than in controls. We suggest that rs7204044 of TSC is a genetic factor for EH in these two ethnicities and that rs13306673 is a genetic factor for EH in the Han population.