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This is an explanatory paper on Sun Il Kwon et al., Nat. Photon. 15: 914-918, 2021 and some parts of this manuscript are translated from the paper. Medical imaging modalities such as X-ray computed tomography, Magnetic resonance imaging, positron emission tomography (PET), and single photon emission computed tomography, require image reconstruction processes, consequently constraining them to form cylindrical shapes. However, among them, only PET can use additional information, so called time of flight, on an event-by-event basis. If coincidence time resolution (CTR) of PET detectors improved to 30 ps, which corresponds to spatial resolution of 4.5 mm, directly localizing electron-positron annihilation point is possible, allowing us to circumvent image reconstruction processes and free us from the geometric constraint. We call this concept direct positron emission imaging (dPEI). We have developed ultrafast radiation detectors by focusing on Cherenkov photon detection. Furthermore, the CTR of 32 ps being equivalent to 4.8 mm spatial resolution is achieved by combining deep learning-based signal processing with the detectors. In this article, we explain how we developed the detectors and demonstrated the first dPEI using different types of phantoms, how we will tackle limitations to be addressed to make the dPEI more practical, and how dPEI will emerge as an imaging modality in nuclear medicine.

Surface grinding workers of Indium Tin Oxide target material are exposed to an indium compound with high toxicity. We divided individual exposure workers into similar exposure groups (SEG) and examined the effectiveness of the classification of SEG. Sampling was carried out twice a day for a total of 10 times, in 9 of which a work environment measurement in unit work area was performed at the same time. The classification examined two methods. One method was to set all the workers in the work place as one group (SEG1), and the other was to classify them depending on whether the workers handled the target material contained indium or not (SEG2). The group handled indium-contained material was SEG2(+) n=9, and the other was SEG2(-) n=9. Only the arithmetic mean value (AM) of four groups 2.8-27.4 µg/m 3 in the SEG2(+) was lower than the measurement B value of the work environment measurement, but the AM of all the groups in SEG2(+) 2.8-276.8 µg/m 3 was higher than the geometric mean value of measurement A 0.4-12.3 µg/m 3 . The concentration range of 100 μg/m 3 or more of SEG2(+) AM was 20% of the total. This range was not recognized in the other items, and the variation of SEG2(+) was small. Even though the evaluation of SEG1 is control class 2, if revaluated on SEG2(+), 50% of the SEG2(+) were evaluated as control class 3. It is possible to efficiently manage chemical substances by establishing specific SEG properly stratified.

The pathophysiology and treatment for renal bone disease have made remakable progress. Moreover, osteocyte reseach has made tremendous progress. In the clinical aspect, (1) hyperphosphatemia, (2) hyperparathyroid and hypoparathyroid bone disease in patients with chronic kidney disease, (3) increased serum level of fibroblast growth factor 23 (FGF-23) and(4) reduced level of Klotho should be taken into consideration when analyzing these conditions. On the other hand, hyperphosphatemia must be successfully treated. Hyperparathyroid bone disease has been successfully treated with vitamin D sterol, cinacalcet hydrochloride and parathyroidectomy, however, the treatment of hypoparathyroidism inpatient with diabetes or non-diabetes met with high hurdles. We must treat these patients in thinking about osteocytic perilacunar/canalicular system.

Vascular endothelial cells(ECs)play a critical role in controlling a variety of vascular functions including maintenance of the vascular tone, blood coagulation and fibrinolysis, and selective permeability of proteins. It has recently become apparent that ECs respond to hemodynamic forces, namely, shear stress and stretch, by altering their morphology, functions and gene expression profile. These responses also play important roles in maintaining normal circulatory system functions and homeostasis, and their impairment leads to various vascular diseases, including hypertension, aneurysm and atherosclerosis. The mechanisms underlying the mechanotransduction, however, are not yet clearly understood. In this article, we review the literature on the EC responses to mechanical forces and their roles in the regulation of the circulatory system, while also discussing the mechanosensing mechanisms of ECs.

Objective: Eye diseases including cataract, keratitis and pterygium have been reported to be sun-exposure-related. The association between macular degeneration and blue light has also been discussed. Moreover, it is hypothesized that retinal exposure to blue light may influence the human circadian rhythm. However, no monitoring devices exist that can measure eye exposure to visible and ultraviolet (UV) radiation over time. To measure the exact dose at specific times, we have developed a novel sensing system (ray-sensing glass system: RaySeG)., Methods: RaySeG can continuously measure and record the composition and intensity of light with a time-stamped system. Subjects wearing RaySeG were instructed to walk under various light conditions such as indoor and outdoor., Results: RaySeG consists of two sensors embedded in the eyeglasses. These sensors are for UV (260-400 nm), visible lights (red, 615 nm; green, 540 nm; and blue, 465 nm: peak wavelength for each). The total weight of the system is about 100 g, and the size is comparable to that of a digital audio player. The system continuously recorded changes in visible and UV light exposure under various conditions., Conclusions: After accuracy validation, further experiments with a larger number of subjects are required. Our final goal is to apply the system to evaluating personal eye exposure to UV and visible light in epidemiological studies of eye diseases and circadian rhythm abnormality.

Establishment of a system that allows selective drug delivery and gene silencing to a tumor is expected to enable targeted therapy. We constructed a genetically modified adenovirus incorporating an IgG Fc-binding motif from the Staphylococcus protein A, Z33 (Adv-FZ33). By cross-linking the Adv-FZ33 virus and the surface antigen molecules with the targeting monoclonal antibodies (mAbs), we attained highly enhanced gene deliveries into the respective antigen-positive cancer cells. Therefore, we aimed to establish a systematic screening method to search for antibody and cell surface target candidates that would provide highly selective anti-cancer reagents to malignant tumors. Using an Adv-FZ33, hybridoma libraries producing a variety of mAbs for human pancreatic, prostate, lung or ovarian carcinoma cells were screened, and we were able to selectively obtain several mAbs which had potent high affinity and recognized antigens of high structure. Within these mAbs, we have identified tumor cell target molecules including not only carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), prostate specific membrane antigen (PSMA) but also novel tumor surface target molecules such as phosphatidic acid phosphatase type 2a (PAP2a) and interleukin-13 receptor variant α2 (IL-13Rα2) as tumor antigens. Overall, these results indicate that this type of inductive method approach is a reliable strategy for screening in antibody therapy on par with antibody-dependent drug-delivery system.

Running for an extended period of time can cause severe stress on the body, subsequently damaging skeletal muscle and resulting in changes in blood components. However, few reports have examined vital responses during and after running. This study analyzed inflammatory responses during and after running and changes in stress responses as determined by serial changes in blood components. Venous blood was obtained before starting, 6 h after starting, 12 h after starting, and immediately after finishing 24 h of continuous running. Samples were analyzed for high-sensitivity C-reactive protein (hsCRP), pentraxin 3 (ptx3), white blood cells (WBC), myoglobin, creatine kinase (CK), and hormones. Diet and physical activity were standardized 24 h before and after running. Subjects comprised 16 men who agreed to participate in experimental running on November 8 and 9, 2008, at Tokyo Gakugei University. Mean running distance was 151.32 +/- 32.1 km (range, 83.6-210.0 km) in 24 h. A significant increase in hsCRP was seen from 12 h after starting to completion. Compared to hsCRP, ptx3 gradually increased from before starting to after completion, showing a significant difference between pre and post-run ptx3 levels. WBC count increased significantly until 6 h after starting. Neutrophils in leukocytosis increased significantly during the first 6 h. Eosinophils decreased significantly over the course of the 24 h. Cortisol increased, and testosterone decreased significantly from 6 h after starting. Dehydroepiandrosterone sulfate (DHEA-S), myoglobin, and CK increased over the course of the 24 h. Reactive oxygen metabolites (d-ROMs) changed within the normal range though there was a significant decrease, and biological anti-oxidant potential (BAP) stabilized. Active natural killer cells decreased significantly after 24 h running. Biopyrrin (BPn) increased significantly. Changes in stress oxide were small both during and after running, and adaptation for antioxidation was good. DHEAS, a biomarker of aging, was found to increase over the course of the 24 h, suggesting that controlling decreases in DHEA-S may be possible using exercise, particularly in males. The key finding was that DHEA S levels tended to increase with continuous aerobic exercise.

The structure and function of blood vessels adapt to environmental changes, for example, physical development and exercise. This phenomenon is based on the ability of endothelial cells (ECs) to sense and respond to blood flow. ECs are in direct contact with blood flow and exposed to shear stress. A number of recent studies have revealed that ECs recognize changes in shear stress and transmit signals to the interior of the cell, which leads to cellular responses that involve changes in cell morphology, cell function, and gene expression. Cultured human pulmonary artery ECs (HPAECs) showed Ca²(+) influx via an ATP-operated cation channel, P2X4, in response to shear stress. We have recently found that shear-induced activation of P2X4 requires endogenously released ATP and that shear stress induced HPAECs to release ATP, which was mediated by cell-surface ATP synthase located in caveolae. To gain insight into its significance, we generated a P2X4-deficient mouse. P2X4(-/-) mice do not exhibit normal EC responses to flow, such as Ca²(+) influx and subsequent production of NO, a potent vasodilator. Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2X4(-/-) mice. Furthermore, P2X4(-/-) mice have higher blood pressure than wild-type mice. Moreover, no adaptive vascular remodeling is observed in the P2X4(-/-) mice. Thus, P2X4-mediated shear stress mechanotransduction plays an important role in the vascular homeostasis, including the control of blood pressure and vascular remodeling.

Our new surgical treatment for corneal endothelial dysfunction involves replacing damaged the corneal endothelium with healthy corneal endothelial cells cultivated and multiplied in vitro. Monkey corneal endothelial cells (MCECs) were cultivated on collagen type- I carriers for four weeks. The corneal endothelium of the monkeys was mechanically scraped, and the cultivated MCEC sheet was inserted into the anterior chamber and fixed to the Descemet's membrane with air. As controls, a collagen sheet without MCECs was transplanted into one eye, and a suspension of cultivated MCECs was injected into the anterior chamber in another eye. In the early postoperative period MCEC sheets were attached to Descemet's membrane and corneal clarity recovered. This was accompanied by a decrease in corneal thickness. Fluorescein DiI labeled donor corneal endothelial cells were detected on the host cornea on postoperative day7. After transplantation, the MCEC-transplanted corneas remained clear for up to 4 years, and hexagonal cells of a density more than 1,500-2,000 cells/mm2 were observed by in vivo specular microscopy. Control eyes showed irreversible bullous keratopathy. We established a model of cultivated corneal endothelial transplantation for corneal endothelial dysfunction in primates whose corneal endothelial cells have less proliferative capacity in vivo. Our results suggest that this is a useful model for long-term observation in advance of future clinical application of cultivated corneal endothelial transplantation.

To identify protein biomarkers linking to disease activity and treatment responses of patients with rheumatoid arthritis (RA), proteomic study using mass spectrometric analysis of plasma proteins was performed. Proteomic profiling technologies can simultaneously resolve and analyze multiple proteins in plasma. Evaluation of multiple proteins of the plasma will be essential to discover protein biomarkers. In this study, we used protein chip surface enhanced laser desorption/ionization time of flight mass spectrometry approach (SELDI-TOF MS). Through differential profiling of plasma proteins, we selected two prospective candidate biomarkers. One mass spectrometric peak distinguished patients with RA from healthy controls was transthyretin (TTR) and the other distinguished inactive patients with RA from patients with active RA was Serum Amyloid A (SAA). This study demonstrates that proteomic profiling using mass spectrometry of plasma greatly facilitates global discovery and verify clinically relevant sets of disease biomarker directly links to disease activity and treatment responses.

The electrical activities of the heart causes weak changes of the magnetic field, which can be recorded as magnetocardiogram (MCG). Fetal cardiac magnetic activity is measured in the order of less than 10 pT. An advance of the novel technology of a superconducting quantum interference device enabled the first recording of fetal MCG (FMCG) in 1974. In Japan, FMCG instrument (MC6400, Hitachi High-Technologies Ltd) was approved as a diagnostic tool by Japanese Government in 2003 owing to the cooperative studies of Tsukuba University, National Cardiovascular Center and Hitachi Ltd. FMCG offers similar information to a fetal electrocardiogram, which is difficult to be recorded because the fetal skin is covered with fatty caseous vernix of weak electrical conductivity in the second and third trimester of pregnancy. Magnetic flux can pass through the fat layer, and thus FMCG can measure the electrical activity of the fetal heart. Besides FMCG has far higher resolutions in time domain than echocardiography does. The amplitude of FMCG signals depends on the size of fetal heart and the distance between the sensors and the fetal heart. The amplitudes of the QRS, P and T waves increases with gestational age. Since the amplitudes of P and T waves are often weak, averaging of FMCG signals is needed to improve the signal-to-noise ratio. Current-arrow map is a useful mapping technique even in FMCG. FMCG has been applied in the prenatal diagnosis of fetal arrhythmias such as bradyarrhythmia (atrioventricular block, long QT syndrome, etc), tachyarrhythmia (supraventricular tachycardia, atrial flutter, atrial fibrillation and WPW syndrome, etc) and extrasystoles. Fetal cardiomegaly with myocardial abnormalities can be also diagnosed by FMCG. Applications of FMCG for fetal heart rate monitoring using beat-to-beat variability have been also studied to obtain better information on fetal well-beings.

The mechanisms by which shear stress elevates intracellular Ca(2+) in endothelial cells (EC) are not fully understood. Here we report that endogenously released ATP contributes to shear stress-induced Ca(2+) responses. Application of a flow of Hank's balanced solution to human pulmonary artery EC (HPAEC) elicited shear stress-dependent increases in Ca(2+) concentration. Chelation of extracellular Ca(2+) with EGTA completely abolished the Ca(2+) responses, whereas the phospholipase C inhibitor U-73122 and the Ca(2+)-ATPase inhibitor thapsigargin had no effect, indicating that the response was due to the influx of extracellular Ca(2+). The Ca(2+) influx was significantly suppressed by apyrase, which degrades ATP, and by antisense oligonucleotide targeted to P2X4 receptors. A luciferase luminometric assay showed that shear stress induced dose-dependent release of ATP. When the ATP release was inhibited by the ATP synthase inhibitors angiostatin or oligomycin, the Ca(2+) influx was markedly suppressed but was restored by removal of these inhibitors or addition of extracellular ATP. These results suggest that shear stress stimulates HPAEC to release ATP, which activates Ca(2+) influx via P2X4 receptors.

Biomaterial is one of the most important factors to be developed in regenerative medicine. In this paper, the biomaterials essential to regenerative medicine were described. Biomaterials in regenerative medicine are classified into 5 categories; 1) Biomaterials for cell culture, 2) Biomaterials for cell inducement, 3) Biomaterials for scaffold, 4) Biomaterials for immuno-isolation, 5) Biomaterials assist to regenerative medicine. As for 1), temperature responsible gel that can take out the cultured cell sheet without use protein breakdown enzyme, is mainly introduced. Micro-photolithography to make a micro patterning for cell inducement, kinds of materials for scaffold, isolated membrane and micro capsules, carrier for cell growth factors are mentioned in 2) to 5).