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More than 800 million people suffer from kidney disease. Genetic studies and follow-up animal models and cell biological experiments indicate the key role of proximal tubule metabolism. Kidneys have one of the highest mitochondrial densities. Mitochondrial biogenesis, mitochondrial fusion and fission, and mitochondrial recycling, such as mitophagy are critical for proper mitochondrial function. Mitochondrial dysfunction can lead to an energetic crisis, orchestrate different types of cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis), and influence cellular calcium levels and redox status. Collectively, mitochondrial defects in renal tubules contribute to epithelial atrophy, inflammation, or cell death, orchestrating kidney disease development., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic repair are poorly understood. We developed a model of adaptive and fibrotic kidney regeneration by titrating ischemic injury dose. We performed detailed biochemical and histological analysis and profiled transcriptomic changes at bulk and single-cell level (> 110,000 cells) over time. Our analysis highlights kidney proximal tubule cells as key susceptible cells to injury. Adaptive proximal tubule repair correlated with fatty acid oxidation and oxidative phosphorylation. We identify a specific maladaptive/profibrotic proximal tubule cluster after long ischemia, which expresses proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors. Druggability analysis highlights pyroptosis/ferroptosis as vulnerable pathways in these profibrotic cells. Pharmacological targeting of pyroptosis/ferroptosis in vivo pushed cells towards adaptive repair and ameliorates fibrosis. In summary, our single-cell analysis defines key differences in adaptive and fibrotic repair and identifies druggable pathways for pharmacological intervention to prevent kidney fibrosis., (© 2022. The Author(s).)

More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Inflammation is an important component of fibrosis but immune processes that orchestrate kidney fibrosis are not well understood. Here we apply single-cell sequencing to a mouse model of kidney fibrosis. We identify a subset of kidney tubule cells with a profibrotic-inflammatory phenotype characterized by the expression of cytokines and chemokines associated with immune cell recruitment. Receptor-ligand interaction analysis and experimental validation indicate that CXCL1 secreted by profibrotic tubules recruits CXCR2 + basophils. In mice, these basophils are an important source of interleukin-6 and recruitment of the T H 17 subset of helper T cells. Genetic deletion or antibody-based depletion of basophils results in reduced renal fibrosis. Human kidney single-cell, bulk gene expression and immunostaining validate a function for basophils in patients with kidney fibrosis. Collectively, these studies identify basophils as contributors to the development of renal fibrosis and suggest that targeting these cells might be a useful clinical strategy to manage chronic kidney disease., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

NAD + is an essential coenzyme for all living cells. NAD + concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD + metabolism across tissues. In aged mice, we observed modest tissue NAD + depletion (median decrease ∼30%). Circulating NAD + precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD + pool was modestly faster such that absolute NAD + biosynthetic flux was maintained, consistent with more active NAD + -consuming enzymes. Calorie restriction partially mitigated age-associated NAD + decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD + by impairing synthesis in both young and aged mice. Thus, the decline in NAD + with normal aging is relatively subtle and occurs despite maintained NAD + production, likely due to increased consumption., Competing Interests: Declaration of interests J.D.R. and J.A.B. are consultants to Pfizer. J.D.R. is an advisor and stock owner in Colorado Research Partners, L.E.A.F. Pharmaceuticals, Rafael Pharmaceuticals, Raze Therapeutics, Kadmon Pharmaceuticals, and Agios pharmaceuticals. J.D.R. is a co-inventor of SHIN2 and related SHMT inhibitors, which have been patented by Princeton University, and is a co-founder of Toran Therapeutics. G.X., M.F.C., and G.J.T. are current or former employees of Pfizer who may hold Pfizer stock and/or stock options. J.A.B. and S.M. are inventors on a patent for using NAD(+) precursors in liver injury and have received research funding and materials from Elysium Health and Metro International Biotech, both of which have an interest in NAD(+) precursors. The remaining authors have nothing to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified hundreds of genetic risk regions for kidney dysfunction [estimated glomerular filtration rate (eGFR)]; however, the causal genes, cell types, and pathways are poorly understood. Integration of GWAS and human kidney expression of quantitative trait analysis using Bayesian colocations, transcriptome-wide association studies, and summary-based Mendelian randomization studies prioritized caspase-9 (CASP9) as a kidney disease risk gene. Human kidney single-cell epigenetic and immunostaining studies indicated kidney tubule cells as a disease-causing cell type. Mice with genetic deletion or pharmacological inhibition of CASP9 showed lower apoptosis while having improved mitophagy, resulting in dampened activation of cytosolic nucleotide sensing pathways (cGAS-STING), reduction of inflammation, and protection from acute kidney disease or renal fibrosis. In summary, here, we prioritized CASP9 as an eGFR GWAS target gene and demonstrated the causal role of CASP9 in kidney disease development via improving mitophagy and lowering inflammation and apoptosis.

Genome-wide association studies (GWAS) for kidney function identified hundreds of risk regions; however, the causal variants, target genes, cell types, and disease mechanisms remain poorly understood. Here, we performed transcriptome-wide association studies (TWAS), summary Mendelian randomization, and MetaXcan to identify genes whose expression mediates the genotype effect on the phenotype. Our analyses identified Dachshund homolog 1 (DACH1), a cell-fate determination factor. GWAS risk variant was associated with lower DACH1 expression in human kidney tubules. Human and mouse kidney single-cell open chromatin data (snATAC-Seq) prioritized estimated glomerular filtration rate (eGFR) GWAS variants located on an intronic regulatory region in distal convoluted tubule cells. CRISPR-Cas9-mediated gene editing confirmed the role of risk variants in regulating DACH1 expression. Mice with tubule-specific Dach1 deletion developed more severe renal fibrosis both in folic acid and diabetic kidney injury models. Mice with tubule-specific Dach1 overexpression were protected from folic acid nephropathy. Single-cell RNA sequencing, chromatin immunoprecipitation, and functional analysis indicated that DACH1 controls the expression of cell cycle and myeloid chemotactic factors, contributing to macrophage infiltration and fibrosis development. In summary, integration of GWAS, TWAS, single-cell epigenome, expression analyses, gene editing, and functional validation in different mouse kidney disease models identified DACH1 as a kidney disease risk gene.

Dachshund homolog 1 (DACH1), a key cell-fate determinant, regulates transcription by DNA sequence-specific binding. We identified diminished Dach1 expression in a large-scale screen for mutations that convert injury-resistant podocytes into injury-susceptible podocytes. In diabetic kidney disease (DKD) patients, podocyte DACH1 expression levels are diminished, a condition that strongly correlates with poor clinical outcomes. Global Dach1 KO mice manifest renal hypoplasia and die perinatally. Podocyte-specific Dach1 KO mice, however, maintain normal glomerular architecture at baseline, but rapidly exhibit podocyte injury after diabetes onset. Furthermore, podocyte-specific augmentation of DACH1 expression in mice protects from DKD. Combined RNA sequencing and in silico promoter analysis reveal conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1 and Pax transactivation-domain interacting protein (Ptip) KO mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach1-binding sites. PTIP, an essential component of the activating histone H3 lysine 4 trimethylation (H3K4Me3) complex, interacts with DACH1 and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increases promoter H3K4Me3. These findings reveal that in DKD, diminished DACH1 expression enhances podocyte injury vulnerability via epigenetic derepression of its target genes.

Background: Understanding the complex anatomy of neurostructures is very important in various stages of medical education, from medical students to experienced neurosurgeons, and, ultimately, for the knowledge of human beings., Objective: To develop an interactive computer graphics (CG) anatomic head model and present the current progress., Methods: Based on the prior head 3-dimensional CG (3DCG) polygon model, 23 additional published papers and textbooks were consulted, and 2 neurosurgeons and 1 CG technician performed revision and additional polygon modeling. Three independent neurosurgeons scored the clear visibility of anatomic structures relevant to neurosurgical procedures (anterior petrosal and supracerebellar infratentorial approaches) in the integrated 3DCG model (i model) and patients' radiological images (PRIs) such as those obtained from computed tomography, magnetic resonance imaging, and angiography., Results: The i model consisted of 1155 parts (.stl format), with a total of 313 763 375 polygons, including 10 times more information than the foundation model. The i model was able to illustrate complex and minute neuroanatomic structures that PRIs could not as well as extracranial structures such as paranasal sinuses. Our subjective analysis showed that the i model had better clear visibility scores than PRIs, particularly in minute nerves, vasculatures, and dural structures., Conclusion: The i model more clearly illustrates minute anatomic structures than PRIs and uniquely illustrates nuclei and fibers that radiological images do not. The i model complements cadaveric dissection by increasing accessibility according to spatial, financial, ethical, and social aspects and can contribute to future medical education., (© Congress of Neurological Surgeons 2021.)

Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model., Competing Interests: Declaration of Interests The Susztak lab is supported by Boehringer Ingelheim, Lilly, Regeneron, GSK, Merck, Bayer, and Gilead for work that is not related to the current manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Dipeptides have attracted much attention as post-amino acids with physical properties and functions different from those of amino acids. However, a given dipeptide cannot be distinguished by mass spectrometry from its structural isomer with an opposite amino acid binding order unless these isomers are separated before introduction, which complicates the comprehensive analysis of dipeptides. Herein, a novel analytical platform for dipeptide analysis by capillary electrophoresis tandem mass spectrometry and liquid chromatography tandem mass spectrometry is developed. This method is used to quantitate 335 dipeptides and achieves excellent separation of structural isomers with opposite binding orders, high correlation coefficients, and low instrumental detection limits (0.088-83.1 nM). Moreover, acceptable recoveries (70-135%) are observed for most tested dipeptides in chicken liver samples spiked both before and after preparation. The developed method is also applied to the quantitation of dipeptides in the livers of mice fed different diets to detect 236 dipeptides, and the shift from a normal diet to a high-fat diet is shown to increase/decrease ( p < 0.05, fold-change < 0.5) the contents of 0/29 dipeptides, respectively. The developed method is expected to facilitate the search for new dipeptide applications such as novel functional components of foods and biomarkers of diseases.

Purpose: We compared three-dimensional (3D) and two-dimensional (2D) measurements of the solid component to determine radiological criteria for sublobar resection of lung adenocarcinoma ≤ 2 cm in size., Methods: We included 233 surgical cases. The maximum size of the solid component for 3D measurement was calculated by delineating the solid component on successive axial images and reconstructing the 3D surface model., Results: The predictive performance for adenocarcinoma in situ (n = 43) and minimally invasive adenocarcinoma (n = 77) were equivalent to areas under the curve of 0.871 and 0.857 for 2D and 3D measurements (p = 0.229), respectively. A solid component of 5 mm had a prognostic impact on both measurements ( ≤ 5 mm versus > 5 mm; p = 0.003 for 2D and p = 0.002 for 3D, log-rank test). Survival rates at 5 years were 94.7-96.9% following lobectomy and sublobar resection among patients with a solid component ≤ 5 mm in size. Sublobar resection resulted in worse survival rates, with declines at 5 years of 15.8% on 2D and 11.5% on 3D measurements, than lobectomy in patients with a solid component > 5 mm in size., Conclusions: A solid component ≤ 5 mm in size is an appropriate criterion for sublobar resection for both measurements. In addition, 2D measurement is justified because of its simple implementation.

High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase - the primary enzyme of fructose - is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Public engagement has become one of the most effective tools in gaining feedback and perspectives from members of the public, involving patients with decisions, and inspiring young people to carry the medical profession forwards. Brainbook is a multi-platform, social media-based resource that was created specifically to enhance public engagement in neurosurgery and results from one of its case discussions will be reported in this paper., Methods: A Brainbook case was created in collaboration with the NIHR Global Health Research Group on Neurotrauma and presented over 3 days (23-25 February 2018). YouTube videos were created depicting the management of an acute subdural haematoma using patient interviews, medical illustration, consultant-led discussion and operative footage. Content was shared across all Brainbook social media platforms and analytics were gathered through social media applications., Results: Over a 72-hour time period, and across multiple social media accounts, 101,418 impressions were achieved (defined as penetrance onto individual media feeds and total views of the content), with active discussion on social media., Conclusions: Neurosurgical content published across multiple social media outlets represents an encouraging and exciting potential for global engagement across multiple audiences. Social media can be an effective method of not only disseminating neurosurgical knowledge, but activating and engaging the public, allied healthcare professionals, medical students and neurosurgeons.

Background: A recent trend has occurred of increased awareness and an emphasis for teaching nontechnical skills (NTSs) in the world of surgery. Although neurosurgery has incorporated simulation-based training as a part of the training curriculum in the United Kingdom, it has yet to formally introduce NTS training. The present study, therefore, queried both neurosurgical trainees and tutors regarding how much they valued NTSs and their development., Methods: We performed a questionnaire-based, mixed-methods study to determine the knowledge, attitudes, and practices of both neurosurgical trainees and tutors regarding NTSs across neurosurgical centers in the United Kingdom in 2015., Results: The trainees valued NTSs and their development more than did their tutor counterparts (P < 0.05, z-testing). This was evident from both the quantitative results and the qualitative data gained from the questionnaire. Various areas for potential improvement of the curriculum were also identified., Conclusion: The results of the present study highlight the importance of NTS development in neurosurgery. These results could act as a good starting point for further larger scale similar studies and discussion on curriculum committees., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression., Materials and Methods: Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done., Results: Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD + level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level., Conclusion: These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The treatment of distal clavicle fracture is always a challenge, as it is mostly unstable and has higher rate of delayed union, malunion, non-union and associated acromioclavicular arthritis. So the management of these fractures remains controversial. The purpose of this study is to evaluate the functional results of Type 2 distal end clavicle fractures treated with superior anterior locking plate., Methods: From June 2011 to August 2015 a retrospective study of12 male patients (mean age of 41.3 years) 11 with unilateral and 1 with bilateral distal clavicle fractures treated with superior anterior locking plate was done. They were evaluated at regular intervals with mean follow up of 14 months(12-18 months). Those with minimum one year follow up were included in our study. All were evaluated for the functioning of the shoulder joint by both Oxford shoulder score and Quick DASH scores, rate of bone union, complications and earliest time for return to work., Results: All fractures union seen within 6-8 weeks (mean time: 7.1 weeks). All had good shoulder range of motion. The average oxford shoulder and Quick DASH score were 46.2 and 6.5. There were no major complications in our study viz. non-union, plate failure, secondary fracture. But one patient had superficial wound infection. All patients returned to work within 3 months of postoperative period., Conclusion: Displaced distal clavicle fractures treated with superior anterior locking plates achieved excellent results in terms of bony union with rarely any complications and demonstrate promising results with this novel technique.

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection.

Purpose: In most orthopedic surgeries, knowing how far to insert surgical tools is crucial. The objective of this study was to provide guidance information on depth without tracking surgical tools. A previously developed laser guidance system for linear surgical tool insertion uses two laser beams that display the insertion point and orientation on the skin surface. However, the system only provides 4 degrees of freedom guidance (an entry point on the planned pathway line and the orientation) but do not inform surgeons on the ideal insertion depth., Method: A 5-DOF guidance method was developed to provide guidance information by direct projection onto the surgical area using laser beams without tracking markers. A position and orientation guidance performed by two laser beams and depth guidance performed by a single laser beam are appeared on the surgical area in turn. However, depth point appears on the surgical tool side face with some error because of tool radius. Using the actual depth position, insertion path vector and location of the laser sources, the correct depth point on the tool's surface is calculated by the proposed method. So, this system can indicate and navigate the 5-DOF which is planning path and the correct depth point., Results: An evaluation of the accuracy of depth guidance revealed a depth guidance error of 0.55±0.29 mm and results from phantom target insertions revealed overall system accuracies of 1.44 ± 1.09 mm, 0.91° ± 0.82°. In addition, overall system accuracies of application feasibility experiment under the X-ray condition were 1.94 ± 0.98mm, 1.39° ± 1.30°., Conclusion: A new surgical tool depth insertion method was developed using a fluorolaser guidance system. This tool informs surgeons of the surgical tool tip depth assuming that the insertion point and orientation are correct. The new method was tested successfully in vitro.

Purpose: To determine risk factors for systemic air embolism by percutaneous computed tomography (CT)-guided lung biopsy., Methods: This case-control study used data from 2216 percutaneous lung biopsy procedures performed over 11 years at 12 institutions in Japan. Systemic air embolism was identified by retrospective review of CT images obtained during and immediately after the procedures. To fulfill our objective, multiple variables were compared between cases and controls with univariate analyses by using Student's t test and Fisher's exact test for numerical and categorical values, respectively. Multivariate logistic regression analysis was then performed using selected variables., Results: Ten cases of systemic air embolism and 2,206 controls were identified. Univariate analyses showed that the lesions in the lower lobe (P = 0.025) and occurrence of parenchymal hemorrhage (P = 0.019) were significant risk factors. Multivariate analysis showed that the use of a larger biopsy needle was a significant risk factor (P = 0.014)., Conclusion: Parenchymal hemorrhage during the procedure, lesions in the lower lobe, and the use of larger biopsy needles may be risk factors for systemic air embolism by percutaneous CT-guided lung biopsy. Our findings may provide clues toward minimizing the risk of this complication.

The analysis of a combined data set, totaling 3.6 × 10(14) stopped muons on target, in the search for the lepton flavor violating decay μ(+) → e(+)γ is presented. The data collected by the MEG experiment at the Paul Scherrer Institut show no excess of events compared to background expectations and yield a new upper limit on the branching ratio of this decay of 5.7 × 10(-13) (90% confidence level). This represents a four times more stringent limit than the previous world best limit set by MEG.

Purpose: Conventional navigation systems for minimally invasive orthopedic surgery require a secondary monitor to display guidance information generated with CT or MRI images. Newer systems use augmented reality to project surgical plans into binocular glasses. These surgical procedures are often mentally challenging and cumbersome to perform., Method: A comprehensive surgical navigation system for direct guidance while minimizing radiation exposure was designed and built. System accuracy was evaluated using in vitro needle insertion experiments. The fluoroscopic-based navigation technique is combined with an existing laser guidance technique. As a result, the combined system is capable of surgical planning using two or more X-ray images rather than CT or MRI scans. Guidance information is directly projected onto the patient using two laser beams and not via a secondary monitor., Results: We performed 15 in vitro needle insertion experiments as well as 6 phantom pedicle screw insertion experiments to validate navigation system accuracy. The planning accuracy of the system was found to be 2.32 mm and 2.28°, while its overall guidance accuracy was found to be 2.40 mm and 2.39°. System feasibility was demonstrated by successfully performing percutaneous pin insertion on phantoms., Conclusion: Quantitative and qualitative evaluations of the fluorolaser navigation system show that it can support accurate guidance and intuitive surgical tool insertion procedures without preoperative 3D image volumes and registration processes.

We present a new result based on an analysis of the data collected by the MEG detector at the Paul Scherrer Institut in 2009 and 2010, in search of the lepton-flavor-violating decay μ(+)e(+)γ. The likelihood analysis of the combined data sample, which corresponds to a total of 1.8×10(14) muon decays, gives a 90% C.L. upper limit of 2.4×10(-12) on the branching ratio of the μ(+)→e(+)γ decay, constituting the most stringent limit on the existence of this decay to date., (© 2011 American Physical Society)

Experiments have been performed to measure the response of a spherical tissue-equivalent proportional counter (TEPC) and a silicon-based LET spectrometer (RRMD-III) to protons with energies ranging from 50-200 MeV. This represents a large portion of the energy distribution for trapped protons encountered by astronauts in low-Earth orbit. The beam energies were obtained using plastic polycarbonate degraders with a monoenergetic beam that was extracted from a proton synchrotron. The LET spectrometer provided excellent agreement with the expected LET distribution emerging from the energy degraders. The TEPC cannot measure the LET distribution directly. However, the frequency mean value of lineal energy, y(-)(f), provided a good approximation to LET. This is in contrast to previous results for high-energy heavy ions where y(-)(f) underestimated LET, whereas the dose-averaged lineal energy, y(-)(D), provided a good approximation to LET.

The LET distributions in front of the 80 cm-thick concrete side shield at the CERF facility were measured with a Si detector telescope (RRMD-III) covered with and without a 1 cm-thick acrylic plate. In these measurements, a slight difference between the LET distributions was seen as a result of recoil protons and/or carbon particles by neutrons. Also, the LET distributions are compared with the micro-dosimetric spectrum (i.e., lineal energy distribution) measured with a cylindrical TEPC under the same conditions.

In 1997, four dosimeter packages, each of which contains two CR-39 plates and 18 TLDs (Mg2SiO4:Tb), were placed inside the MIR Space Station and flew on an orbit with an inclination angle of 51.6 degrees and an altitude of approximately 400 km for 40 days. We estimated the absorbed doses, dose equivalents and effective quality factors during the flight by combining CR-39 data and TLD data. We then compared these results to those obtained with the same analysis method from the dosimeter packages on board Space Shuttle missions STS-79, -84 and -91 that flew along the same orbit. Finally, the differences between our results and those obtained by another group using passive dosimeters on the MIR are discussed., (c2002 Elsevier Science Ltd. All rights reserved.)

The LET distributions during the Space Shuttle missions STS-84 (altitude 270-412 km, average 375 km; inclination angle, 51.6 degrees) and STS-91 (altitude 328-397 km, average 373 km; inclination angle, 51.6 degrees) were measured using CR-39 plastic nuclear track detectors. A correction for the dip-angle dependence of the track-formation sensitivity of the CR-39 plates was applied to the data analysis. The absorbed doses and the dose equivalents around RRMD Detector Units, estimated from the LET distributions in the LET region of 4-200 keV/micrometers, fluctuated with standard deviations of +/- 21% to +/- 35% in both flight experiments. The LET distributions obtained from the CR-39 plates agreed well with that obtained from RRMD-II in STS-91. However, the particle fluxes obtained from RRMD-III in STS-84 and STS-91 were two or three times higher than those obtained from RRMD-II and the CR-39 plates. It was concluded that the LET distributions obtained from RRMD-II and the CR-39 plates in the present flight experiments did not include the contribution of target-fragmented secondary heavy particles produced by low-LET particles, such as relativistic or semi-relativistic protons and helium ions, whereas RRMD-III was able to detect these secondary particles because of its low triggering level., (c 2002 Elsevier Science Ltd. All rights reserved.)

Determinations of the LET distribution, phi(L), of charged particles within a spacecraft in low-Earth orbit have been made. One method used a cylindrical tissue-equivalent proportional counter (TEPC), with the assumption that for each measured event, lineal energy, y, is equal to LET and thus phi(L) = phi(y). The other was based on the direct measurement of LETs for individual particles using a charged-particle telescope consisting of position-sensitive silicon detectors called RRMD-III. There were differences of up to a factor of 10 between estimates of phi(L) using the two methods on the same mission. This caused estimates of quality factor to vary by a factor of two between the two methods.

Dosimetric measurements on the Space Shuttle Missions STS-84, -89 and -91 have been made by the real-time radiation monitoring device III (RRMD-III). Simultaneously, another dosimetry measurement was made by the Dosimetry Telescope (DOSTEL) on STS-84 and by the tissue-equivalent proportional counter (TEPC) on STS-91. First, the RRMD-III instrument is described in detail and its results summarized. Then, the results of DOSTEL and TEPC are compared with those of the RRMD-III. Also, the absorbed doses obtained by TLD (Mg2SiO4) and by RRMD-III on board STS-84 and -91 are compared., (c2001 Elsevier Science Ltd. All rights reserved.)

A new type of real-time radiation monitoring device, RRMD-III, consisting of three double-sided silicon strip detectors (DSSDs), has been developed and tested on-board the Space Shuttle mission STS-84. The test succeeded in measuring the linear energy transfer (LET) distribution over the range of 0.2 keV/micrometer to 600 keV/micrometer for 178 h. The Shuttle cruised at an altitude of 300 to 400 km and an inclination angle of 51.6 degrees for 221.3 h, which is equivalent to the International Space Station orbit. The LET distribution obtained for particles was investigated by separating it into galactic cosmic ray (GCR) particles and trapped particles in the South Atlantic Anomaly (SAA) region. The result shows that the contribution in dose-equivalent due to GCR particles is almost equal to that from trapped particles. The total absorbed dose rate during the mission was 0.611 mGy/day; the effective quality factor, 1.64; and the dose equivalent rate, 0.998 mSv/day. The average absorbed dose rates are 0.158 mGy/min for GCR particles and 3.67 mGy/min for trapped particles. The effective quality factors are 2.48 for GCR particles and 1.19 for trapped particles. The absorbed doses obtained by the RRMD-III and a conventional method using TLD (Mg(2)SiO(4)), which was placed around the RRMD-III were compared. It was found that the TLDs showed a lower efficiency, just 58% of absorbed dose registered by the RRMD-III.

The measurement of the directional distribution of incident particles was made by using the Real time Radiation Monitoring Device (RRMD)-III placed inside the Space Shuttle STS-84 cruised at an altitude of 400 km and an inclination angle of 51.6 degrees, which are the same as the cruising orbit of the International Space Station (ISS). The directional distributions of incident particles were evaluated over the observed linear energy transfer (LET) range (1-100 keV/micrometers). The pitch angle distribution is also obtained using the geomagnetic model of IGRF-95. The result is roughly in good agreement with the distribution obtained by the VF1-MIN anisotropy model calculation within the present experimental errors, if the shielding distribution is assumed to be uniform.

Space radiation dosimetry measurements have been made on board the Space Shuttle. A newly developed active detector called "Real-time Radiation Monitoring Device (RRMD)" was used (Doke et al., 1995; Hayashi et al., 1995). The RRMD results indicate that low Linear Energy Transfer (LET) particles steadily penetrate around the South Atlantic Anomaly (SAA) without clear enhancement of dose equivalent and some daily periodic enhancements of dose equivalent due to high LET particles are seen at the lower geomagnetic cutoff regions (Doke et al., 1996). We also have been analyzing the space weather during the experiment, and found that the anomalous high-energy particle enhancement was linked to geomagnetic disturbance due to the high speed solar wind from a coronal hole. Additional analysis and other experiments are necessary for clarification of these phenomena. If a penetration of high-energy particles into the low altitude occurs by common geomagnetic disturbances, the prediction of geomagnetic activity becomes more important in the next Space Station's era.

The second flight of the International Microgravity Laboratory (IML-2) on Space Shuttle flight STS-65 provided a unique opportunity for the intercomparison of a wide variety of radiation measurement techniques. Although this was not a coordinated or planned campaign, by sheer chance, a number of space radiation experiments from several countries were flown on this mission. There were active radiation measuring instruments from Japan and US, and passive detectors from US, Russia, Japan, and Germany. These detectors were distributed throughout the Space Shuttle volume: payload bay, middeck, flight deck, and Spacelab. STS-65 was launched on July 8, 1994, in a 28.45 degrees x 306 km orbit for a duration of 14 d 17 hr and 55 min. The crew doses varied from 0.935 mGy to 1.235 mGy. A factor of two variation was observed between various passive detectors mounted inside the habitable Shuttle volume. There is reasonable agreement between the galactic cosmic ray dose, dose equivalent and LET spectra measured by the tissue equivalent proportional counter flown in the payload bay with model calculations. There are significant differences in the measurements of LET spectra measured by different groups. The neutron spectrum in the 1-20 MeV region was measured. Using fluence-dose conversion factors, the neutron dose and dose equivalent rates were 11 +/- 2.7 microGy/day and 95 +/- 23.5 microSv/day respectively. The average east-west asymmetry of trapped proton (>3OMeV) and (>60 MeV) dose rate was 3.3 and 1.9 respectively.

Space radiation dosimetry measurements have been made onboard the Space Shuttle STS-65 in the Second International Microgravity Laboratory (IML-2: 28.5 degrees x 300 km: 14.68 days) and the STS-79 in the 4th Shuttle MIR mission (S/MM#4: 51.6 degrees x 300-400km: 10.2 days). In these measurements, three kinds of detectors were used; one is a newly developed active detector telescope called "Real-time Radiation Monitoring Device (RRMD-I for IML-2 and RRMD-II with improved triggering system for S/MM#4)" utilizing silicon semi-conductor detectors and the other detectors are conventional passive detectors of thermoluminescence dosimeters (TLDs) and CR-39 plastic track detectors. The main contribution to dose equivalent for particles with LET > 5.0 keV/micrometer (IML-2) and LET > 3.5 keV/micrometer (S/MM#4) is seen to be due to galactic cosmic rays (GCRs) and the contribution of the South Atlantic Anomaly (SAA) is less than 5% (IML-2: 28.5 degrees x 300 km) and 15% (S/MM#4: 51.6 degrees x 400 km) in the above RRMD LET detection conditions. For the whole LET range (> 0.2 kev/micrometer) obtained by TLDs and CR-39 in these two typical orbits (a small inclination x low altitude and a large inclination x high altitude), absorbed dose rates range from 94 to 114 microGy/day, dose equivalent rates from 186 to 207 microSv/day and average quality factors from 1.82 to 2.00 depending on the locations and directions of detectors inside the Spacelab at the highly protected IML-2 orbit (28.5 degrees x 300 km), and also, absorbed dose rates range from 290 to 367 microGy/day, dose equivalent rates from 582 to 651 microSv/day and average quality factors from 1.78 to 2.01 depending on the dosimeter packages around the RRMD-II "Detector Unit" at the S/MM#4 orbit (5l.6 degrees x 400km). In general, it is seen that absorbed doses depend on the orbit altitude (SAA trapped particles contribution dominant) and dose equivalents on the orbit inclination (GCR contribution dominant). The LET distributions obtained by two different types of active and passive detectors, RRMDs and CR-39, are in good agreement for LET of 15 - 200 kev/micrometer and difference of these distributions in the regions of LET < 15 kev/micrometer and LET > 200 kev/micrometer can be explained by considering characteristics of CR-39 etched track formation especially for the low LET tracks and chemical etching conditions.

The real-time measurement of radiation environment was made with an improved real-time radiation monitoring device (RRMD)-II onboard Space Shuttle STS-79 (S/MM#4: 4th Shuttle MIR Mission, at an inclination angle of 51.6 degrees and an altitude of 250-400km) for 199 h during 17-25 September, 1996. The observation of the detector covered the linear energy transfer (LET) range of 3.5-6000 keV/micrometer. The Shuttle orbital profile in this mission was equivalent to that of the currently planned Space Station, and provided an opportunity to investigate variations in count rate and dose equivalent rate depending on altitude, longitude, and latitude in detail. Particle count rate and dose equivalent rate were mapped geographically during the mission. Based on the map of count rate, an analysis was made by dividing whole region into three regions: South Atlantic Anomaly (SAA) region, high latitude region and other regions. The averaged absorbed dose rate during the mission was 39.3 microGy/day for a LET range of 3.5-6000 keV/micrometer. The corresponding average dose equivalent rates during the mission are estimated to be 293 microSv/day with quality factors from International Commission on Radiological Protection (ICRP)-Pub. 60 and 270 microSv/day with quality factors from ICRP-Pub. 26. The effective quality factors for ICRP-Pub. 60 and 26 are 7.45 and 6.88, respectively. From the present data for particles of LET > 3.5keV/micrometer, we conclude that the average dose equivalent rate is dominated by the contribution of galactic cosmic ray (GCR) particles. The dose-detector depth dependence was also investigated.

Space radiation dosimetry measurements have been made on board the Space Shuttle. A newly developed active detector called "Real-time Radiation Monitoring Device (RRMD)" was used (Doke et al., 1995; Hayashi et al., 1995). The RRMD results indicate that low Linear Energy Transfer (LET) particles steadily penetrate around the South Atlantic Anomaly (SAA) without clear enhancement of dose equivalent and some daily periodic enhancements of dose equivalent due to high LET particles are seen at the lower geomagnetic cutoff regions (Doke et al., 1996). We also have been analyzing the space weather during the experiment, and found that the anomalous high-energy particle enhancement was linked to geomagnetic disturbance due to the high speed solar wind from a coronal hole. Additional analysis and other experiments are necessary for clarification of these phenomena. If a penetration of high-energy particles into the low altitude occurs by common geomagnetic disturbances, the prediction of geomagnetic activity becomes more important in the next Space Station's era.

A new telescope consisting of three two-dimensional position-sensitive silicon detectors which can measure the linear energy transfer (LET) distribution over the range from 0.2 to 400keV/micrometers has been developed as a real-time radiation monitor in manned spacecraft. First, the principle of LET measurement and its design method are described. Second, suitable electronic parameters for the LET measurement are experimentally determined. Finally the telescope performance is investigated by using, relativistic heavy ions. The first in-flight test of this type of telescope on the US Space Shuttle (STS-84) is scheduled for May, 1997.

Space radiation dosimetry measurements have been made on board the Space Shuttle STS-65 in the Second International Microgravity Laboratory (IML-2). In these measurements, three kinds of detectors were used; one is a newly developed active detector telescope called "Real-time Radiation Monitoring Device (RRMD)" utilizing silicon semi-conductor detectors and others are conventional detectors of thermoluminescence dosimeters (TLDs) and CR-39 plastic track detectors. Using the RRMD detector, the first attempt of real-time monitoring of space radiation has been achieved successfully for a continuous period of 251.3 h, giving the temporal variations of LET distribution, particle count rates, and rates of absorbed dose and dose equivalent. The RRMD results indicate that a clear enhancement of the number of trapped particles is seen at the South Atlantic Anomaly (SAA) without clear enhancement of dose equivalent, while some daily periodic enhancements of dose equivalent due to high LET particles are seen at the lower geomagnetic cutoff regions for galactic cosmic ray particles (GCRs). Therefore, the main contribution to dose equivalent is seen to be due to GCRs in this low altitude mission (300 km). Also, the dose equivalent rates obtained by TLDs and CR-39 ranged from 146.9 to 165.2 microSv/day and the average quality factors from 1.45 to 1.57 depending on the locations and directions of detectors inside the Space-lab at this highly protected orbit for space radiation with a small inclination (28.5 degrees) and a low altitude (300 km). The LET distributions obtained by two different detectors, RRMD and CR-39, are in good agreement in the region of 15-200 keV/mm and difference of these distributions in the regions of LET < 15 keV/mm and LET > 200 keV/mm can be explained by considering characteristics of CR-39 etched track formation especially for the low LET tracks.

Objective: A previous study suggested that temporary occlusion of a segment of the hepatic vein causes an increase in arterial flow and retrograde portal flow in the occluded segment. Such occlusions might improve the efficacy of arterial infusion therapy. Accordingly, we studied the change in blood flow visible on hepatic arteriograms when a segment of the hepatic vein is temporarily occluded in patients with hepatocellular carcinoma., Materials and Methods: The study group consisted of 24 patients with nodular-type hepatocellular carcinoma. Conventional hepatic arteriography was followed by hepatic arteriography performed using a balloon catheter to occlude the hepatic vein that was most closely associated with the tumor. Visualization of the tumor-draining veins, portal vein branches, the degree of tumor vascularity, and the density of the hepatogram on the hepatic arteriogram were retrospectively compared before and during venous occlusion. The veins were evaluated visually; an increase of tumor vascularity was defined as an increase in the number of countable tumor vessels during occlusion, and a dense hepatogram was considered to be a definite sinusoidgram induced by venous occlusion., Results: Conventional hepatic arteriography showed the tumor-draining veins to be branches of the portal vein in only two of the 24 patients (8%). Hepatic arteriography during venous occlusion, however, showed the tumor-draining veins to be branches of the portal vein in four of the patients (17%). An increase in the degree of tumor vascularity with venous occlusion was observed only in a patient with an initial arteriohepatic vein shunt. Dense hepatogram and hepatofugal opacification of the portal vein branches in the occluded, tumor-bearing segment were obtained in 10 patients (42%). Eight of these did not have liver cirrhosis, whereas all of the remaining 14 patients did (p < .001)., Conclusion: Our results suggest that occlusion of a segment of the hepatic vein may be useful during arterial infusion of hepatocellular carcinoma.

During IML-1 mission, we carried out space experiments on radiobiological effect of a single HZE cosmic particle. In the experiment, the precise determination of the distance between the center of the particle trajectory and the individual biological objects around it is an indispensable condition. For the detection of HZE particles CR-39 track detectors were used and analyzed by the video image processing. The positions of biological objects in relation to a particle trajectory were measured by referring to the laser grid marks which were printed on the surface of CR-39 detector. We describe such an experimental method and report the applicability of this method.