Initial evaluation of dynamic human imaging using18F-FRP170 as a new PET tracer for imaging hypoxia

18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxia imaging agent for positron emission tomography. This compound was synthesized by 18F-labeling of RP170, which was developed as a new hydrophilic 2-nitroimidazole analog. In the present study, we analyzed dynamic whole-body imaging in healthy volunteers and dynamic tumor imaging in three patients with lung cancer. METHODS: Four healthy male volunteers and three lung cancer patients were enrolled in this study. Volunteers underwent dynamic whole-body scans just after injection of 18F-FRP170 for about 90 min, while the lung cancer patients underwent dynamic tumor imaging for about 60 or 120 min. Data are expressed as standardized uptake values (SUV). Regions of interest were placed over images of each organ or tumor to generate time-SUV curves. RESULTS: The series of dynamic whole-body scans showed rapid elimination of 18F-FRP170 from the kidneys following elimination from the liver. Very low physiological uptake was observed above the diaphragm. 18F-FRP170 uptake in the lung cancer lesion could be visualized clearly from early after injection. The changes of tumor SUV, tumor/blood ratio, or tumor/muscle ratio about 30 min after injection or later were small. CONCLUSIONS: Dynamic imaging using 18F-FRP170 demonstrated rapid elimination from the kidney, suggesting the high hydrophilicity of this imaging agent. The background activity above the diaphragm was very low, and patients with lung cancer showed clear tumor uptake of 18F-FRP170 early after injection.     

Evaluation of portosystemic shunt caused by patent ductus venosus through sequential whole-body scanning using per-sigmoid colon 123I-IMP scintigraphy

Objective The correct estimation of the portosystemic shunt (PSS) ratio prior to surgery for patent ductus venosus is important. Until now, formulas using the lung and liver uptake for per-rectal portal scintigraphy using ¹²³I-iodoamphetamine (IMP) have been mainly used for calculating the PSS ratio. However, these methods did not take radioactivity in the brain or changes in organ radioactivity over time into consideration. Here, we performed sequential whole-body scanning by per-sigmoid colon ¹²³I-IMP scintigraphy, and evaluated the changes in radioactivity in the liver, lungs, and brain over time. Methods The patient was 7-year-old boy with a patent ductus venosus. A 10 Fr. catheter was inserted into the sigmoid colon under fluoroscopic guidance, through which about 55.5 MBq of ¹²³I-IMP was administered. Following the administration, the patient was placed in the supine position and sequential whole-body scanning (from head to thigh) was performed for up to about 80 min. Four regions of interest (ROIs) were placed on the whole brain, lungs, liver, and mediastinum. The PSS ratios were calculated using both the traditional formula (PSS index: brain uptake is not considered) and our original formula (new index: brain uptake is considered). Results Prior to surgery, the radioactivity could be seen clearly in the brain and lungs just following the injection. The liver uptake was faint on the first and second scans (15 min/scan), and increased gradually over time. In contrast, almost no radioactivity was detected in the brain or lungs following surgery. The liver uptake could be seen clearly just following the injection. The new index was significantly higher than the PSS index. Both the new index and the PSS index showed changes over time especially prior to surgery. Conclusions Distinct brain radioactivity was observed early following administration in a patient with PSS. The calculation of the PSS fraction should be performed taking the brain radioactivity into consideration. The timing of the scan should be fixed, but 30 min following administration may be too early to begin scanning.     

Effects of acute exposure to a 1439 MHz electromagnetic field on the microcirculatory parameters in rat brain

THE AIM of this study was to determine the potential of radio-frequency electromagnetic fields (RF-EMF) to affect cerebral microcirculation, including blood-brain barrier function, in rat brain. MATERIALS AND METHODS: The head of the rat was exposed for 10 min to 1439 MHz RF-EMF having three intensity doses: 0.6, 2.4, 4.8 W/kg of brain averaged specific absorption rate (BASAR). Four microcirculatory parameters: blood-brain barrier permeability, leukocyte behavior, plasma velocity, and vessel diameter were measured before and after RF-EMF exposure using a closed cranial window method. RESULTS: No extravasation of intravenously injected dyes from pial venules was found at any BASAR level. No significant changes in the number of endothelial-adhering leukocytes after exposure were found. The hemodynamics indicated that the plasma velocities and vessel diameters remained constant within the physiological range throughout each exposure. CONCLUSION: These findings suggest that there were no effects on the cerebral microcirculation under the given RF-EMF exposure conditions.     

Long-term observation of pial microcirculatory parameters using an implanted cranial window method in the rat

The aim of this study was to confirm whether our improved closed cranial window (CCW) method could be used for long-term microscopical observation of pial microcirculation intravitally in the rat. We investigated chronological changes in three microcirculatory parameters: permeability of blood-brain barrier, leukocyte behavior, and plasma velocities in the pial venules, immediately after implantation (control group) and at one and four weeks after implantation in different age-matched rats (implanted group). No extravasation of sodium fluorescein from pial venules was confirmed in any observation period. The number of endothelial-adhering leukocytes in the implanted group kept within the physiological range, being similar to those of the control group. The velocities of fluorescent microspheres flowing in pial venules showed no noticeable changes between the two groups. These findings suggest that our CCW method allows long-term observation of the pial microcirculation without any pathophysiological changes in the evaluated parameters up to four weeks after the implantation.     

Life style-related diseases of the digestive system: gene expression in nonalcoholic steatohepatitis patients and treatment strategies

Nonalcoholic steatohepatitis (NASH) is a subset of nonalcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. We analyzed the expression profiles of approximately 50,000 genes and biological pathways in NASH patients in comparison with simple steatosis patients by using the analytical technique of GSEA (Gene Set Enrichment Analysis) by DNA microarrays. Although expressions of various genes were altered, GSEA showed clearly lower expression of nuclear receptors, including the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway. In a preliminary study we therefore investigated the therapeutic effect of low-dose pioglitazone (15 mg/day per body for 24 weeks), a synthetic ligand for PPARgamma, in 12 NASH patients. A decrease in aminotransferase (ALT) values to within the normal range was observed in 7 (58.3%) of the patients, and because the dose of pioglitazone was lower than that ordinarily used, no side effects, such as fatigue, lower extremity edema, or weight gain, were observed. In conclusion, the results confirmed involvement of the PPARgamma pathway in NASH and the therapeutic utility of a PPARgamma ligand.     

Serum total cholesterol levels and risk of mortality from stroke and coronary heart disease in Japanese: the JACC study

The relation between serum total cholesterol and coronary heart disease is well established, but the relations with total stroke and stroke subtypes are controversial. We conducted a nested case-control study as part of the JACC study. A total of 39,242 subjects, 40-79 years of age, provided serum samples at baseline between 1988 and 1990. During the 10-year follow-up, 345 deaths from total strokes (including 76 intraparenchymal hemorrhages) and 150 deaths from coronary heart diseases were recorded. The control subjects were matched for sex, age, community, and year of serum storage, and further adjusted for systolic blood pressure, high density lipoprotein (HDL)-cholesterol, ethanol intake category, smoking status, and diabetes. Serum total cholesterol levels were measured using an enzymatic method. Cases with total stroke and more specifically intraparenchymal hemorrhage had lower mean values of serum total cholesterol levels compared with control subjects. The risk of mortality from intraparenchymal hemorrhage was significantly higher for persons with low total cholesterol levels [less than 4.14 mmol/l (160 mg/dl)] than with those with higher levels. The risk of mortality from coronary heart disease for persons with serum total cholesterol levels more than or equal to 6.72 mmol/l (260 mg/dl) was significantly higher than those with levels less than 4.14 mmol/l (160 mg/dl). Low serum total cholesterol levels are associated with high mortality from intraparenchymal hemorrhage while high levels are associated with high mortality from coronary heart disease among Japanese.     

Human and mouse induced pluripotent stem cells are differentially reprogrammed in response to kinase inhibitors

Conventional human induced pluripotent stem cells (hiPSCs), reprogrammed from somatic cells by induced expression of Oct4, Sox2, Klf4, and c-Myc, are phenotypically different from mouse embryonic stem cells (ESCs). In mice, culture in N2B27 serum-free 2i media (mitogen-activated protein kinase/extracellular signal-regulated kinase and glycogen synthase kinase 3 inhibitors; PD0325901 and CHIR99021) plus leukemia inhibitory factor (LIF) (2i+LIF medium) enriches for germline competent ESCs. Here, we demonstrate that flat-shaped hiPSC colonies can be reprogrammed into bowl-shaped multi-potent stem cells (2i-hiPSCs) by using 2i+LIF medium. Mechanical dissociation of 2i-hiPSC colonies enables stable maintenance for >20 passages. Importantly, gene expression profiling demonstrated that 2i-hiPSCs more closely resemble primitive neural stem cells (PNSCs). Notably, this 2i-induced phenotype was generated from conventional hiPSCs, but not human ESCs (hESCs), thus correlating with the observation of neuroectodermal SOX1-positive colonies in conventional hiPSCs, but not hESCs in 2i+LIF medium. Thus, 2i-hiPSCs, which are nonteratoma forming PNSCs, may represent a safe source of cells for neural research and regenerative medicine.     

Mechanical allodynia but not thermal hyperalgesia is impaired in mice deficient for ERK2 in the central nervous system

Extracellular signal-regulated kinase (ERK) plays critical roles in pain plasticity. However, the specific contribution of ERK2 isoforms to pain plasticity is not necessarily elucidated. Here we investigate the function of ERK2 in mouse pain models. We used the Cre-loxP system to cause a conditional, region-specific, genetic deletion of Erk2. To induce recombination in the central nervous system, Erk2-floxed mice were crossed with nestin promoter-driven cre transgenic mice. In the spinal cord of resultant Erk2 conditional knockout (CKO) mice, ERK2 expression was abrogated in neurons and astrocytes, but indistinguishable in microglia compared to controls. Although Erk2 CKO mice showed a normal baseline paw withdrawal threshold to mechanical stimuli, these mice had a reduced nociceptive response following a formalin injection to the hind paw. In a partial sciatic nerve ligation model, Erk2 CKO mice showed partially restored mechanical allodynia compared to control mice. Interestingly, thermal hyperalgesia was indistinguishable between Erk2 CKO and control mice in this model. In contrast to Erk2 CKO mice, mice with a targeted deletion of ERK1 did not exhibit prominent anomalies in these pain models. In Erk2 CKO mice, compensatory hyperphosphorylation of ERK1 was detected in the spinal cord. However, ERK1 did not appear to influence nociceptive processing because the additional inhibition of ERK1 phosphorylation using MEK (MAPK/ERK kinase) inhibitor SL327 did not produce additional changes in formalin-induced spontaneous behaviors in Erk2 CKO mice. Together, these results indicate that ERK2 plays a predominant and/or specific role in pain plasticity, while the contribution of ERK1 is limited.     

Evaluation of SAR in a human body model due to wireless power transmission in the 10 MHz band

This study discusses a computational method for calculating the specific absorption rate (SAR) due to a wireless power transmission system in the 10 MHz frequency band. A two-step quasi-static method comprised of the method of moments and the scalar potential finite-difference method are proposed. The applicability of the quasi-static approximation for localized exposure in this frequency band is discussed by comparing the SAR in a lossy dielectric cylinder computed with a full-wave electromagnetic analysis and the quasi-static approximation. From the computational results, the input impedance of the resonant coils was affected by the existence of the cylinder. On the other hand, the magnetic field distribution in free space and considering the cylinder and an impedance matching circuit were in good agreement; the maximum difference in the amplitude of the magnetic field was 4.8%. For a cylinder-coil distance of 10 mm, the difference between the peak 10 g averaged SAR in the cylinder computed with the full-wave electromagnetic method and our quasi-static method was 7.8%. These results suggest that the quasi-static approach is applicable for conducting the dosimetry of wireless power transmission in the 10 MHz band. With our two-step quasi-static method, the SAR in the anatomically based model was computed for different exposure scenarios. From those computations, the allowable input power satisfying the limit of a peak 10 g averaged SAR of 2.0 W kg(-1) was 830 W in the worst case exposure scenario with a coil positioned at a distance of 30 mm from the chest.