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Background For several variants of quasi-moyamoya disease, cerebral revascularization treatment is as effective as it is for the more typical cases of moyamoya disease. Here, we examined a case of moyamoya disease with concurrent congenital rubella syndrome (CRS). On the basis of concurrent underlying disease, the patient was considered to have quasi-moyamoya disease and was treated with cerebral revascularization. Case Description A 36-year-old female presented with a large cerebral infarction. She was diagnosed with quasi-moyamoya disease on the basis of clinical and imaging features. The ischemic symptoms and cognitive dysfunction improved after combined direct and indirect revascularization. Conclusions To our knowledge, this is the first known report of moyamoya disease with concurrent CRS. We treated this patient with revascularization as typical for other quasi-moyamoya conditions including Down syndrome. This case emphasizes the effectiveness of revascularization treatment for moyamoya disease with concurrent CRS for the prevention of ischemic stroke and improvement of cognitive function, despite existing cerebral infarction.

Background The incidence of penetrating intracranial foreign bodies is rare, and to date, not many relevant studies have been published worldwide. In particular, a nail penetrating intracranially, just near the superior sagittal sinus (SSS), is extremely rare. We treated the case of a large nail that penetrated the middle of the head and strategized its removal. Case Description A 70-year-old man had experienced headache lasting a day. Computed tomography of the brain revealed a nail penetrating the middle of his head; in particular, the tip of the nail had penetrated the right ventricle, causing a slight subarachnoid hemorrhage. Angiography showed that the nail was very close to the SSS and that the venous flow was normal. However, there was a risk of the nail penetrating through the SSS or injuring other arteries, and we removed the nail directly from the intracranial view to stop bleeding from the SSS or other vessels. Fortunately, there was no bleeding, and we washed the hole created by the nail penetration and concluded the surgery. Conclusions Our technique is useful and safe for removing large nails penetrating the head.

Pollen sampling has been performed using various sampling methods around the world. However, the sampling efficiencies of these methods remain unclear. In this study, we compared the sampling efficiency of a Sigma-2 two-layered aerosol sampling inlet and a Hirst-style wind vane inlet to reveal the relationship between sampling efficiency and samplers’ physical characteristics. The initial results show a higher sampling efficiency for the former. To further explore this finding, we developed a theory based on 1) continuity equations for pollen grain concentrations and 2) impaction theory. Applying our developed theory to the experimental results revealed that impaction is a significant contributor to the relatively higher sampling efficiency of the two-layered sampling inlet, due to the larger cross-sectional area of the two-layered inlet and slower sampled pollen grain speed within the sampler. Additionally, applying a correction based on the theoretical impaction effects improved the experimental results. Our experiment demonstrated the possibility of a pollen sampler showing discrepancies in airborne pollen concentrations and explained the mechanism of this inaccuracy. The application of these results to pollen sampling will aid understanding of actual airborne pollen concentration.

Background Chronic subdural hematoma (CSDH) is the most common disease encountered in neurosurgery. Diagnoses of CSDH are usually made on the basis of computed tomography (CT) images. In this report, we discuss the case of a patient with meningioma whose findings instead suggested CSDH. Case Description A 91-year-old woman complained of dizziness. Brain CT imaging revealed a low-density subdural space, following which we diagnosed her with CSDH. On the same day, we performed burr hole surgery. However, when opening the burr hole and cutting the dura, a light yellowish tumor was observed under the dura. After the operation, her condition deteriorated and she died 2 days later. After 10 days, pathologic examination of the tumor specimen led to a diagnosis of atypical meningioma. Conclusions In almost all cases, CSDH can be diagnosed using CT images only. However, our patient's true diagnosis was meningioma, rather than CSDH. We rouse attention not to take it for CSDH with a CT image easily.

Background Current worldwide clinical practice guidelines recommend acetaminophen as the first option for the treatment of acute low back pain. However, there is no concrete evidence regarding whether acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) is more effective for treating acute low back pain (LBP) in Japan. The present study aimed to investigate whether acetaminophen treatment for acute musculoskeletal pain was comparable with loxoprofen (a traditional NSAID in Japan) treatment. Methods Of the 140 patients with acute LBP who visited out-patient hospitals, 127 were considered eligible and were randomly allocated to a group taking acetaminophen or one taking loxoprofen. As primary outcome measure, pain intensity was measured using a 0–10-numeric rating scale (NRS). Moreover, pain disability, pain catastrophizing, anxiety, depression, and quality of life, as well as adverse events, were assessed as secondary outcomes. The primary outcome was tested with a noninferiority margin (0.84 on changes in pain-NRS), and the secondary outcomes were compared using conventional statistical methods at week 2 and week 4. Results Seventy patients completed the study (acetaminophen: 35, loxoprofen: 35). The dropout rates showed no significant difference between the two medication-groups. We found that the mean differences of changes in pain-NRS from baseline to week 2 or 4 between the two medication groups were not statistically beyond the noninferiority margin (mean [95% confidence interval]: −0.51 [−1.70, 0.67], at week 2 and −0.80 [−2.08, 0.48] at week 4). There were no consistent differences between the two medication groups in terms of secondary outcomes. Conclusions The results suggest that acetaminophen has comparable analgesic effects on acute LBP, based on at least a noninferiority margin, compared with loxoprofen at 4 weeks. Acetaminophen seems to be a reasonable first-line option for patients with acute LBP in Japan.

Evaluating airborne pollen concentrations is important for the understanding of the spatiotemporal dispersion of pollen grains. Using two identical pollen monitors in parallel, we performed two experiments in order to study the influences of a) the physical characteristics (orientation) of the air inlet and b) the presence of obstacles in proximity to the monitors on airborne pollen concentration data. The first experiment consisted of an evaluation of airborne pollen concentrations using two different types of orifices; 1) a vertically oriented inlet and 2) a wind vane intake, both attached to the same type of automatic pollen sampler. The second experiment investigated the relationship between vertical wind speed and horizontal wind direction around an obstacle with the goal of studying the impact of micro-scale wind on pollen sampling efficiency. The results of the two experiments suggest that the wind path near an obstacle might be redirected in a vertical direction before or after the wind flows over the obstacle, which causes measurement errors of airborne pollen concentrations that are proportional to the vertical wind speed, especially when a vertically oriented inlet is used.

Aim Intracranial metastases from uterine leiomyosarcoma, particularly solitary skull metastases, are very rare, with only five cases reported to date. In this study, we present our experience with the treatment of these lesions, along with a review of the previously reported cases. To the best of our knowledge, this represents the first review of cases of skull metastasis from uterine leiomyosarcoma. Material and Methods We examined three patients with skull metastases from uterine leiomyosarcomas. Planning their treatment was challenging because of the lack of literature on such cases. Results Gross tumor resection with a 1-cm surgical margin was performed in all three cases. One of the patients also received postoperative radiation therapy. In two cases, there was no recurrence until the 15-month follow-up. The third patient developed two recurrences within a short period, and after two operations, she was treated with nivolumab. Genomic analysis was also performed in one case. Conclusions Due to the lack of effective chemotherapy, skull metastasis from uterine leiomyosarcoma has a poor prognosis. However, in cases where genomic analysis does not indicate a poor prognosis, surgical treatment may be effective and is recommended.

In this paper, a stochastic system based Bayesian approach is applied to quantify the uncertainties involved in the modeling of the HCN/O2/Ar mixture kinetics proposed by Thielen and Roth (1987). This enables more robust predictions of quantities of interest such as rate coefficients of HCN + Ar → H + CN + Ar and O2 + CN → NCO + O by using a stochastic Arrhenius form calibrated against their experimental data. This Bayesian approach requires the evaluation of multidimensional integrals, which cannot be done analytically. Here a recently developed stochastic simulation algorithm, which allows for efficient sampling in the high-dimensional parameter space, is used. We quantify the uncertainties in the modeling of the HCN/O2/Ar mixture kinetics and in turn the two rate coefficients and the other relevant rate coefficients. The uncertainty in the error including both the experimental measurement error and physical modeling error is also quantified. The effect of the number of uncertain parameters on the uncertainties is investigated.

Background The financial burden of medical insurance on the government of Japan has recently become severe, which has led to the control of outpatient orthopedic reimbursements for common procedures. On the other hand, the overall disease burden for total hip or knee arthroplasty, decompression for cervical myelopathy or lumbar spinal canal stenosis, and new surgical technologies to treat other painful conditions and the post-surgical care related to these procedures has been reduced. Methods Medical insurance systems in Japan are generally influenced by budget-balancing action. Consequently, the further development of interventional evaluation methods should be promoted. From the viewpoint of health economics, the value (meaning) of medical intervention can partly be explained by its cost-effectiveness. In order for appropriate medical reimbursement levels to be set for orthopedic surgery, the financial status of medical institutions needs to be concurrently reviewed. In particular, the relationship between the expense structure and medical reimbursement must be discussed to evaluate its role in community medicine system. Results Over the past 10 years, medical expenditures have increased by 9.6% in all fields, whereas the monthly medical reimbursements per patient have dropped by an average of 17.5%. Remarkably, surgery-related costs have increased by 36.5%, while other medical costs have decreased by 19.8%. There are a few reports of cost-utility analyses which investigate interventions such as total hip arthroplasty for hip osteoarthritis patients (US$ 4,600–70,500/QALY) and laminectomy for patients with spinal canal stenosis. Interventions may be an inevitable part of relative expense control under the current trend; however, there has been a slight increase in other parameters in response to changes in medical reimbursement evaluations - specifically, in the total income of medical institutions. Conclusions If medical professionals such as orthopedic surgeons contribute to the economic value of orthopedic surgery, it is crucial to clearly establish interventions among the different performances of medical reimbursement to motivate the increased allocation of management resources. To further develop this concept, discussions between stakeholders should involve the value of medicine based on cost and benefit.

The validation process proposed by Babuska et al. 1 is applied to thermochemical models describing post-shock flow conditions. In this validation approach, experimental data is involved only in the calibration of the models, and the decision process is based on quantities of interest (QoIs) predicted on scenarios that are not necessarily amenable experimentally. Moreover, uncertainties present in the experimental data, as well as those resulting from an incomplete physical model description, are propagated to the QoIs. We investigate four commonly used thermochemical models: a one-temperature model (which assumes thermal equilibrium among all inner modes), and two-temperature models developed by Macheret et al. 2, Marrone and Treanor 3, and Park 4. Up to 16 uncertain parameters are estimated using Bayesian updating based on the latest absolute volumetric radiance data collected at the Electric Arc Shock Tube (EAST) installed inside the NASA Ames Research Center. Following the solution of the inverse problems, the forward problems are solved in order to predict the radiative heat flux, QoI, and examine the validity of these models. Our results show that all four models are invalid, but for different reasons: the one-temperature model simply fails to reproduce the data while the two-temperature models exhibit unacceptably large uncertainties in the QoI predictions.

SummaryIsolation of specific cell types, including pluripotent stem cell (PSC)-derived populations, is frequently accomplished using cell surface antigens expressed by the cells of interest. However, specific antigens for many cell types have not been identified, making their isolation difficult. Here, we describe an efficient method for purifying cells based on endogenous miRNA activity. We designed synthetic mRNAs encoding a fluorescent protein tagged with sequences targeted by miRNAs expressed by the cells of interest. These miRNA switches control their translation levels by sensing miRNA activities. Several miRNA switches (miR-1-, miR-208a-, and miR-499a-5p-switches) efficiently purified cardiomyocytes differentiated from human PSCs, and switches encoding the apoptosis inducer Bim enriched for cardiomyocytes without cell sorting. This approach is generally applicable, as miR-126-, miR-122-5p-, and miR-375-switches purified endothelial cells, hepatocytes, and insulin-producing cells differentiated from hPSCs, respectively. Thus, miRNA switches can purify cell populations for which other isolation strategies are unavailable.

Dendritic cell (DC) vaccine is a promising immunotherapy for cancer due to its ability to induce antigen-specific CTLs efficiently. However, a number of clinical studies have implied insufficient therapeutic benefits with the use of MHC class 1 restricted peptide-pulsed DC vaccine. To enhance the clinical efficacy, we examined combination therapy of DC vaccine pulsed with OVA peptide and intravenous low dose unmodified IL-2 (IL-2 solution) administration against EG7 tumor-bearing mice. Unexpectedly, no additional effects of IL-2 solution were observed on CTL induction and the therapeutic effects of DC vaccine, possibly because of the short half-life of IL-2 in plasma. Therefore, we generated IL-2-encapsulating polymeric micelles (IL-2 micelle), which showed prolonged IL-2 retention in the circulation after intravenous administration compared with IL-2 solution. When mice were treated with OVA peptide-pulsed DCs in combination with IL-2 micelle, OVA-specific CTLs were efficiently induced in the spleen in comparison with DC vaccine combined with IL-2 solution or DC vaccine alone. In addition, combination therapy of DC vaccine and IL-2 micelle against EG7 tumor-bearing mice induced the efficient accumulation of antigen-specific CTLs into the tumor and marked anti-tumor effects. Thus, the administration of IL-2 micelle can significantly enhance DC vaccine efficacy against tumors.

In many cases, model validation requires that legacy data be partitioned into calibration and validation sets, but how to do so is a nontrivial and open area of research. We present a systematic procedure to partition the data, adapted from cross-validation and in the context of predictive modeling. By considering all possible partitions, we proceed with post-processing steps to find the optimal partition of the data subject to given constraints. We are concerned here with mathematical models of physical systems whose predictions of a given unobservable quantity of interest are the basis for critical decisions. Thus, the proposed approach addresses two critical issues: (1) that the model be evaluated with respect to its ability to reproduce the data and (2) that the model be highly challenged by the validation set with respect to predictions of the quantity of interest. This framework also relies on the interaction between the experimentalist and/or modeler, who understand the physical system and the limitations of the model; the decision-maker, who understands and can quantify the cost of model failure; and the computational scientists, who strive to determine if the model satisfies both the modeler's and decision-maker's requirements. The framework is general and may be applied to a wide range of problems. It is illustrated here through an example using generated experiments of a nonlinear one degree-of-freedom oscillator.

A stochastic Bayesian approach is applied to investigate the uncertainty in the rate coefficient of H + O 2 → OH + O ( k 1 ) using the latest shock-tube experimental data. We simultaneously calibrate all random variables using a recently developed stochastic simulation algorithm which allows for efficient sampling in the high-dimensional parameter space. We introduce the idea of “irreducible” uncertainty when considering other parameters in the system. Nine stochastic models are constructed depending on the choice of uncertainties, hydrogen concentration, gas temperature, pressure, and rate coefficients of other reactions. The sensitivity analysis of uncertainty in k 1 on these uncertainty parameters is performed. It is shown that the introduction of “irreducible” uncertainty does not always increase the uncertainty of k 1 . In addition, we observe the high sensitivity of uncertainty in k 1 to the uncertainty in the measured time-shift. Our results show the strong temperature dependence of the uncertainty in the rate coefficient.

Experimental raw data provided by measuring instruments often need to be converted into meaningful physical quantities through data reduction modeling processes in order to be useful for comparison with outputs of computer simulations. These processes usually employ mathematical models that have to be properly calibrated and rigorously validated so that their reliability can be clearly assessed. A validation procedure based on a Bayesian approach is applied here to a data reduction model used in shock tube experiments. In these experiments, the raw data, given in terms of photon counts received by an ICCD camera, are post-processed into radiative intensities. Simple mathematical models describing the nonlinear behavior associated with very short opening times (gate widths) of the camera are developed, calibrated, and not invalidated, or invalidated, in this study. The main objective here is to determine the feasibility of the methodology to precisely quantify the uncertainties emanating from the raw data and from the choice of the reduction model. In this analysis of the methodology, shortcomings, suggested improvements, and future research areas are also highlighted. Experimental data collected at the Electric Arc Shock Tube (EAST) facility at the NASA Ames Research Center (ARC) are employed to illustrate the validation procedure.

In this paper, a stochastic system based Bayesian approach is applied to estimate different model parameters and hence quantify the uncertainty of a graphite nitridation experiment. The Bayesian approach is robust due to its ability to characterize modeling uncertainties associated with the underlying system and is rigorous due to its exclusive foundation on the axioms of probability theory. We choose an experiment by Zhang et al. [1] whose main objective is to measure the reaction efficiency for the active nitridation of graphite by atomic nitrogen. To obtain the primary physical quantity of interest, we need to model and estimate the uncertainty of a number of other physical processes associated with the experimental setup. We use the Bayesian method to obtain posterior probability distributions of all the parameters relevant to the experiment while taking into account uncertainties in the inputs and the modeling errors. We use a recently developed stochastic simulation algorithm which allows for efficient sampling in the high-dimensional parameter space. We show that the predicted reaction efficiency of the graphite nitridation and its uncertainty is ∼3.1 ± 1.0 × 10−3 that is slightly larger than the ones deterministically obtained by Zhang et al. [1] .

We present a Monte Carlo (MC) model of [OI] 6300 A and [SII] 6716 A emission from Io entering eclipse. The simulation accounts for the 3-D distribution of SO 2 , O, SO, S, and O 2 in Io’s atmosphere, several volcanic plumes, and the magnetic field around Io. Thermal electrons from the jovian plasma torus are input along the simulation domain boundaries and move along the magnetic field lines distorted by Io, occasionally participating in collisions with neutrals. We find that the atmospheric asymmetry resulting from varying degrees of atmospheric collapse across Io (due to eclipse ingress) and the presence of volcanoes contributes significantly to the unique morphology of the [OI] 6300 A emission. The [OI] radiation lifetime of ∼134 s limits the emission to regions that have a sufficiently low neutral density so that intermolecular collisions are rare. We find that at low altitudes (typically 4 × 10 9 cm −3 ) to collisionally quench nearly all (>95%) of the excited oxygen for reasonable quenching efficiencies. Upstream (relative to the plasma flow), Io’s perturbation of the jovian magnetic field mirrors electrons with high pitch angles, while downstream collisions can trap the electrons. This magnetic field perturbation is one of the main physical mechanisms that results in the upstream/downstream brightness asymmetry in [OI] emission seen in the observation by Trauger et al. (Trauger, J.T., Stapelfeldt, K.R., Ballester, G.E., Clarke, J.I., 1997. HST observations of [OI] emissions from Io in eclipse. AAS-DPS Abstract (1997DPS29.1802T)). There are two other main causes for the observed brightness asymmetry. First, the observation’s viewing geometry of the wake spot crosses the dayside atmosphere and therefore the wake’s observational field of view includes higher oxygen column density than the upstream side. Second, the phased entry into eclipse results in less atmospheric collapse and thus higher collisional quenching on the upstream side relative to the wake. We compute a location (both in altitude and latitude) for the intense wake emission feature that agrees reasonably well with this observation. Furthermore, the peak intensity of the simulated wake feature is less than that observed by a factor of ∼3, most likely because our model does not include direct dissociation–excitation of SO 2 and SO. We find that the latitudinal location of the emission feature depends not so much on the tilt of the magnetic field as on the relative north/south flux tube depletion that occurs due to Io’s changing magnetic latitude in the plasma torus. From 1-D simulations, we also find that the intensity of [SII] 6716 and 6731 A emission is much weaker than that of [OI] even if the [SII] excitation cross section is 10 3 times larger than excitation to [OI]. This is because the density of S + is much less than that of O and because the Einstein- A coefficient of the [SII] emission is a factor of ∼10 smaller than that of [OI].

A large-eddy simulation (LES) model with a new localized dynamic subgrid closure for the magnetohydrodynamics (MHD) equations is used to investigate plasma-assisted combustion in supersonic flow. A 16-species and 74-reactions kinetics model is used to simulate hydrogen-air combustion and high-temperature air dissociation. The numerical model is validated with experimental data for non-reacting and reacting supersonic flow over a rearward-facing step. The creation of a plasma source near the step corner is shown to have a strong localized effect with the high temperature region resulting in an increase of the radical species concentration in the mixing region. This has the potential for enhancing combustion. In addition, downstream fuel–air mixing is improved, primarily by the creation of a strong baroclinic torque effect in the near field of the plasma source. Furthermore, by adding an uniform external magnetic field, the Lorentz force effect helps to further enhance mixing by lifting the shear layer and increasing fuel penetration by approximately 20%.

Background Recent studies have revealed that Glasgow prognostic score (GPS), an inflammation-based prognostic score, is associated with poor outcome in a variety of tumors. However, few studies have investigated whether GPS measured prior to neoadjuvant chemoradiotherapy (nCRT) is useful for postoperative prognosis of patients with advanced esophageal squamous cell carcinoma (ESCC). Methods GPS was calculated on the basis of admission data as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminaemia (

We determined the relationship between the serum concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) in 33 patients with subacute sclerosing panencephalitis (SSPE) to investigate the function of the blood-brain-barrier (BBB) in SSPE. Serum MMP-9 and TIMP-1 levels were measured by ELISA. Serum MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients in Papua New Guinea (n = 24), and those in Japan (n = 9) were significantly higher than the each control (MMP-9, p = 0.0390, and p = 0.0023, respectively; MMP-9/TIMP-1, p = 0.0319, and p = 0.0009, respectively). Serum MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients with Jabbour stage III (n = 13) were significantly higher than those with Jabbour stage II (n = 18) (p = 0.003, and p = 0.0412, respectively). There were no significant differences of serum TIMP-1 levels between the SSPE patients and controls. High serum MMP-9 and MMP-9/TIMP-1 levels will promote brain invasion through the BBB by immunocompetent cells in the blood. Our findings suggest that the balance of serum MMP-9 and TIMP-1 levels modulate the inflammatory cascade of SSPE.

Measles AIK-C vaccine strain exhibits temperature-sensitivity (ts). To identify the structural proteins, which contribute to the ts property of AIK-C virus, reverse genetics was used. MV-minigenome RNA was replicated at 32.5, 37, and 39 degrees C when the plasmids expressing N, P, and L proteins of the Edmonston strain (the parental strain of AIK-C) were used, whereas the minigenome RNA replicated only at 32.5 degrees C but did not at 37 degrees C and higher temperature when N, P, and L protein expression plasmids of the AIK-C strain were used. A series of minigenome experiments revealed that the amino acid substitution of leucine at position 439 of the P protein by proline (P439-Pro) contributes to the ts phenotype of AIK-C. Four recombinant viruses having various P genes were rescued from the modified AIK-C genome cDNA and ts-characteristics were compared in Vero cells by plaque formation assay. The results showed that the P439-Pro of AIK-C virus played a key role in the ts phenotype, but the other substitutions in the P gene might have an accessory function in the expression of the phenotype.

Background Subacute sclerosing panencephalitis (SSPE) is a rare progressive inflammatory disease characterized by the persistent infection of the brain by the measles virus. However, the immunological pathophysiology of SSPE is still unclear. Methods We measured the concentrations of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in the serum and cerebrospinal fluid (CSF) of 23 patients with SSPE in Papua New Guinea (PNG), a country with a high incidence of SSPE, and Japanese controls by cytometric bead array or ELISA. Results The serum IL-6 and IL-10 levels of SSPE patients were significantly higher than those of controls ( p = 0.0075, and p = 0.0019, respectively). The serum IL-6 and IL-10 levels of SSPE patients with fever were significantly higher than those without fever ( p = 0.0107, and p = 0.0006, respectively). The CSF IL-6 levels of SSPE patients were significantly higher than those of controls ( p = 0.0218). The CSF IL-6 levels of SSPE patients with myoclonic jerks were significantly higher than those without myoclonic jerks ( p = 0.0189). There were no differences in serum IFN-γ, TNF-α, IL-2, IL-4, and sTNFR1, or CSF IFN-γ, TNF-α, IL-2, IL-4, IL-10, and sTNFR1 levels between the affected patients and controls. Conclusion Our present study suggests that serum IL-6 and IL-10 levels are related to fever, and the CSF IL-6 level, myoclonic jerks, in SSPE patients in PNG.

Volcanic plumes on Jupiter's moon Io are modeled using the direct simulation Monte Carlo (DSMC) method. The modeled volcanic vent is interpreted as a “virtual” vent. A parametric study of the “virtual” vent gas temperature and velocity is performed to constrain the gas properties at the vent by observables, particularly the plume height and the surrounding condensate deposition ring radius. Also, the flow of refractory nano-size particulates entrained in the gas is modeled with “overlay” techniques which assume that the background gas flow is not altered by the particulates. The column density along the tangential line-of-sight and the shadow cast by the plume are calculated and compared with Voyager and Galileo images. The parametric study indicates that it is possible to obtain a unique solution for the vent temperature and velocity for a large plume like Pele. However, for a small Prometheus-type plume, several different possible combinations of vent temperature and velocity result in both the same shock height and peak deposition ring radius. Pele and Prometheus plume particulates are examined in detail. Encouraging matches with observations are obtained for each plume by varying both the gas and particle parameters. The calculated tangential gas column density of Pele agrees with that obtained from HST observations. An upper limit on the size of particles that track the gas flow well is found to be ∼ 10 nm , consistent with Voyager observations of Loki. While it is certainly possible for the plumes to contain refractory dust or pyroclastic particles, especially in the vent vicinity, we find that the conditions are favorable for SO2 condensation into particles away from the vent vicinity for Prometheus. The shadow cast by Prometheus as seen in Galileo images is also reproduced by our simulation. A time averaged frost deposition profile is calculated for Prometheus in an effort to explain the multiple ring structure observed around the source region. However, this multiple ring structure may be better explained by the calculated deposition of entrained particles. The possibility of forming a dust cloud on Io is examined and, based on a lack of any such observed clouds, a subsolar frost temperature of less than 118 K is suggested.

The incomplete differentiation of human induced pluripotent stem cells (iPSCs) poses a serious safety risk owing to their potential tumorigenicity, hindering their clinical application. Here, we explored the potential of phospho-D-peptides as novel iPSC-eliminating agents. Alkaline phosphatases overexpressed on iPSCs dephosphorylate phospho-D-peptides into hydrophobic peptides that aggregate and induce cell death. We isolated a peptide candidate, D-3, that selectively and rapidly induced toxicity in iPSCs within 1 hr but had little influence on various non-iPSCs, including primary hepatocytes and iPSC-derived cardiomyocytes. Two hours of D-3 treatment efficiently eliminated iPSCs from both single cultures and co-cultures spiked with increasing ratios of iPSCs. In addition, D-3 prevented residual iPSC-induced teratoma formation in a mouse tumorigenicity assay. These results suggest the enormous potential of D-3 as a low-cost and effective anti-iPSC agent for both laboratory use and for the safe clinical application of iPSC-derived cells in regenerative medicine.

Chronic-constriction injury (CCI) of the sciatic nerve causes mechanical and heat hyperalgesia and mechanical allodynia in the plantar surface of the hindpaw. The underlying mechanism thought to account for these phenomena include central sensitization induced by peripheral nerve injury, ie, the increase in neuronal activity of spinal dorsal horn neurons. As a marker of neuronal activation of the central nervous system, Fos expression has been used widely to monitor the change in neuronal activity evoked by peripheral input. In this study, we examined the antinociceptive effect of electroacupuncture (EA) on pain behavior and noxious stimulus-evoked Fos expression in dorsal horn neurons of the spinal cord in CCI rats 14 days after injury. Male Sprague-Dawley rats (180 to 200 g) received loose ligation of the left sciatic nerve. Heat and mechanical hyperalgesia and mechanical allodynia were examined by the plantar foot test, the pin-prick test, and the von Frey test before and after the EA treatment (100 Hz, 0.3 millisecond, 3 or 1 mA, 20 minutes) into the Zusanli point (S36). When EA stimulation to the Zusanli point was applied, the mechanical and heat hyperalgesia were significantly suppressed; however, mechanical allodynia was not affected. The EA stimulation to nonacupuncture point did not show any significant effect. Next, pinch stimulation was applied to the plantar surface of the operated hindpaw of the CCI rats for 10 minutes, and the stimulus-evoked Fos expression in dorsal horn neurons in L4-L6 spinal cord levels was then examined by using immunohistochemistry. The number of noxious stimulus-evoked Fos-labeled neurons in both the superficial and deep laminae of the dorsal horn in the CCI rats was increased significantly compared with those in sham-operated rats, suggesting an increased excitability of dorsal horn neurons to noxious stimuli. Concurrent EA treatment to the Zusanli point with the pinch stimulus suppressed the increase in the number of Fos-labeled cells in the spinal dorsal horn in the CCI rats. The present results show that EA treatment has antinociceptive effects on both pain behavior and neuronal activation of the spinal dorsal horn neurons in CCI rats. © 2001 by the American Pain Society

Low-threshold sensory pathways have been suggested to have an important role in the formation and maintenance of sensory abnormalities which are observed after peripheral nerve injury. Fos-like immunoreactive (Fos-LI) neurons are expressed in spinal cord laminae III–IV and the gracile nucleus by electrically stimulating the injured nerves at Aβ strength after sciatic nerve transection in rats. This suggests that the excitability of these neurons is increased by nerve injury. In this study, we investigated which receptors are involved in the regulation of the increased excitability in spinal and gracile nucleus neurons. The sciatic nerve of Sprague–Dawley rats (150 g) was transected 7 days before the experiment day. The rats were administered morphine, muscimol, baclofen, MK-801, CNQX, NG-nitro- l -arginine methyl ester hydrochloride ( l -NAME) or clonidine i.p., and then electrically stimulated at 0.1 mA to the proximal region to the nerve injury site under urethane anesthesia. Two hours after the stimulation, Fos-LI expression was increased in the spinal cord dorsal horn and the gracile nucleus in control rats. Baclofen inhibited the Fos-LI expression both in the spinal cord and the gracile nucleus. Morphine inhibited only the Fos-LI expression in the posterior cutaneous (PC) nerve territory of laminae I–II, but not in the sciatic nerve (SC) territory, laminae III–IV nor the gracile nucleus. MK-801 had an inhibitory but complicated effect in laminae I–II and the gracile nucleus. The other drugs were not effective on Fos-LI expression. It is suggested that the GABAB receptor has a pivotal role in the regulation of Fos-LI expression after electrical stimulation to the injured low-threshold sensory fibers, and other receptors have little effect on the Fos-LI expression.

Spinal and cranial motoneurons express alpha- and beta-calcitonin gene-related peptide (CGRP) mRNAs constitutively at variable ratios, and these two mRNAs are differentially regulated following axotomy in spinal, facial, and hypoglossal motoneurons. The purpose of this study was to investigate the change in CGRP mRNA expression following nerve injury in oculomotor, trochlear, abducens, and trigeminal motor nuclei in which beta-CGRP mRNA is predominantly expressed under normal conditions. Using male Sprague-Dawley rats, either the left eyeball and the orbital contents including the bulbar muscles were removed, or the left masseter nerve was ligated and transected. The rats were allowed to survive for 1, 3, 7, 14, 28, 56 days following these procedures. The levels of mRNAs for alpha- and beta-CGRP and growth-associated protein (GAP)-43 were analyzed by in situ hybridization histochemistry using 35S-labeled oligonucleotide probes. Following nerve injury, the expression of alpha-CGRP mRNA rapidly increased on the directly-injured side in all of these nuclei. Thereafter, it gradually decreased and returned to about the control level at postoperative day 56 within oculomotor, trochlear, and abducens motoneurons, but it sustained at a high level within trigeminal motoneurons. The expression of beta-CGRP was quite variable among these nuclei, and significant changes were also seen on the side contralateral to the directly-injured side. These data indicate that the up-regulation of alpha-CGRP mRNA may be a common response of cranial motor neurons following axotomy even if the constitutive expression of beta-CGRP mRNA exceeds that of alpha-CGRP mRNA in these neurons.

Peripheral tissue injury is known to induce changes in gene expression in spinal neurons and result in a prolonged alteration of neuronal excitability. The purpose of this study was to examine the effect of halothane on the dynorphin mRNA expression in spinal dorsal horn neurons after peripheral tissue injury by formalin injection and compare the effect to that of ketamine and nitrous oxide. Male Sprague–Dawley rats were anesthetized with 1.3% halothane, ketamine, or 67% nitrous oxide. Fifteen minutes after induction of anesthesia, rats received an intraplantar injection of 150 μl 5% formalin into the unilateral hindpaw. General anesthesia was maintained for 8 h, and the expression of preprodynorphin (PPD) and preproenkephalin (PPE) mRNAs in the spinal cord (L4-5) was examined by in situ hybridization. The degree of edema of the inflamed foot was not different among the three anesthesia groups and the control (no anesthesia) group. The number of neurons expressing PPD mRNA dramatically increased in the superficial dorsal horn ipsilateral to the formalin injection in the control group compared to the contralateral side. The number of neurons labeled for PPD mRNA in the halothane group was significantly less than the control group. However, the number of PPD mRNA-expressing neurons in both the ketamine and nitrous oxide groups was significantly less than the halothane group. The expression of PPE mRNA was not influenced by these anesthetics. These data indicate that the suppressive effect of halothane anesthesia on the induction of PPD mRNA in dorsal horn neurons was smaller than those of ketamine and nitrous oxide, suggesting an important supplemental way to control the alteration of gene expression in spinal neurons for clinical settings.

Background: Major histocompatibility complex class 1-related chain A/B (MIC A/B), expressed on the cell-surface of cancer cells, functions as a ligand for NKG2D, an important immunoreceptor expressed on gamma delta (γδ) T cells. We investigated the effect of gemcitabine (GEM), a key drug for pancreatic cancer treatment, on the expression of cellsurface MIC A/B in pancreatic cancer cells and resulting cytotoxity of γδ T cells. Materials and Methods: We investigated the effect of GEM on the upregulation of cell-surface MICA/ B expression by flow cytometry, utilizing seven pancreatic cancer cell lines. MICA and CD16 (γδ T and NK cells) expression from resected pancreatic cancer patient specimens, which received neoadjuvant chemotherapy (NAC) with GEM, was analyzed by immunohistochemistry. Results: At a concentration not affecting cell growth, GEM increased the MICA/B expression effectively on all pancreatic cancer cell lines. Furthermore, GEM increased the MICA/B expression at a cytostatic concentration but did not increase the MICA/B expression at a cytotoxic concentration in the PANC-1 cell line (Fig.1A,B). Moreover, cytotoxic activity of γδT cells against PANC-1 was detected and function via NKG2D and MICA/B interaction. Immunohistochemical staining demonstrated that MICA expression in tumor cells (Fig.1C) and CD16 positive cells surrounding tumors (Fig.1D) were significantly higher in the NAC group compared to that of the control group. There was a significant correlation between NAC and MICA expression (p=0.002), as well as NAC and CD16 positive cell expression (p=0.001). Conclusion: The present results indicate that low dose GEM-induced MICA/B expression activates innate immune function, rather than cytotoxicity in pancreatic cancer.

Kinetic modeling of 99mTc-diethylenetriaminepentaacetic acid galactosyl human serum albumin (Tc-GSA) measures the total amount of asialoglycoprotein receptor within a subject's liver. This study tested the hypothesis that the amount of asialoglycoprotein receptor measured by Tc-GSA modeling provides a valid index of functional liver mass.Twenty-two patients with cirrhosis, 18 patients with chronic hepatitis, and 9 patients with normal liver parenchyma were studied with Tc-GSA using a 30-min dynamic imaging protocol. The total amount of hepatic receptor was measured by kinetic modeling of the Tc-GSA time-activity data. The total number of viable hepatocytes was calculated using standard morphometric measurements of liver biopsy samples and liver volume measurements through CT.The total receptor amount strongly correlated with the total hepatocyte number (r = 0.803; P0.0001).Tc-GSA measurement of the total receptor amount is proportional to the number of viable hepatocytes and therefore provides a valid assessment of functional liver mass.