OBJECTIVE: To evaluate the effect of photobiomodulation (PBM) on the drainage of brain interstitial fluid (ISF) and to investigate the possible mechanism of the positive effect of PBM on Alzheimer's disease (AD). METHODS: Twenty-four SD male rats were randomly divided into PBM group (n=12), sham PBM group (n=6), and negative control group (n=6). According to the injection site of tracer, the PBM group was further divided into PBM-ipsilateral traced group (n=6) and PBM-contralateral traced group (n=6). Rats in the PBM group and the sham PBM group were exposed to the dura minimally invasively on the skull corresponding to the frontal cortical area reached by ISF drainage from caudate nucleus region. The PBM group was irradiated by using 630 nm red light (5-6 mW/cm²), following an irradiation of 5 min with a 2 min pause, and a total of 5 times; the sham PBM group was kept in the same position for the same time using the light without power. The negative control group was kept without any measure. After PBM, tracer was injected into caudate nucleus of each group. The changes of ISF drainage in caudate nucleus were observed according to the diffusion and distribution of tracer molecule by tracer-based magnetic resonance imaging, and the structural changes of brain extracellular space (ECS) were analyzed by diffusion rate in ECS-mapping (D_ECS-mapping) technique. Finally, parameters reflecting the structure of brain ECS and the drainage of ISF were obtained: volume fraction (α), tortuo-sity (λ), half-life (T_1/2), and D_ECS. The differences of parameters among different groups were compared to analyze the effect of PBM on brain ECS and ISF. One-Way ANOVA post hoc tests and independent sample t test were used for statistical analysis. RESULTS: The parameters including T_1/2, D_ECS, and λ were significantly different among the PBM-ipsilateral traced group, the PBM-contralateral traced group, and the sham PBM group (F=79.286, P < 0.001; F=13.458, P < 0.001; F=10.948, P=0.001), while there was no difference in the parameter α of brain ECS among the three groups (F=1.217, P=0.324). Compared with the sham PBM group and the PBM-contralateral traced group, the PBM-ipsilateral traced group had a significant decrease in the parameter T_1/2 [(45.45±6.76) min vs. (76.01±3.44) min, P < 0.001; (45.45±6.76) min vs. (78.07±4.27) min, P < 0.001], representing a significant acceleration of ISF drainage; the PBM-ipsilateral traced group had a significant increase in the parameter D_ECS [(4.51±0.77)×10^-4 mm²/s vs. (3.15±0.44)×10^-4 mm²/s, P < 0.001; (4.51±0.77)×10^-4 mm²/s vs. (3.01±0.38)×10^-4 mm²/s, P < 0.001], representing a significantly increased molecular diffusion rate of in the brain ECS; the PBM-ipsilateral traced group had a significant decrease in the parameter λ (1.51±0.21 vs. 1.85±0.12, P=0.001; 1.51±0.21 vs. 1.89±0.11, P=0.001), representing a significant decrease in the degree of tortuosity in the brain ECS. CONCLUSION PBM can regulate the brain ISF drainage actively, which may be one of the potential mechanisms of the effect of PBM therapy on AD. This study provides a new method for enhancing the brain function via ECS pathway.
Animals ; Male ; Rats ; Alzheimer Disease ; Brain ; Drainage ; Extracellular Fluid ; Gadolinium DTPA/metabolism* ; Low-Level Light Therapy ; Rats, Sprague-Dawley

Hair cells at the base of the cochlea appear to be more susceptible to damage by the aminoglycoside gentamicin than those at the apex. However, the mechanism of base-to-apex gradient ototoxicity by gentamicin remains to be elucidated. We report here that gentamicin caused rodent cochlear hair cell damages in a time- and dose-dependent manner. Hair cells at the basal turn were more vulnerable to gentamicin than those at the apical turn. Gentamicin-conjugated Texas Red (GTTR) uptake was predominant in basal turn hair cells in neonatal rats. Transient receptor potential vanilloid 1 (TRPV1) and 4 (TRPV4) expression was confirmed in the cuticular plate, stereocilia and hair cell body of inner hair cells and outer hair cells. The involvement of TRPV1 and TRPV4 in gentamicin trafficking of hair cells was confirmed by exogenous calcium treatment and TRPV inhibitors, including gadolinium and ruthenium red, which resulted in markedly inhibited GTTR uptake and gentamicin-induced hair cell damage in rodent and zebrafish ototoxic model systems. These results indicate that the cytotoxic vulnerability of cochlear hair cells in the basal turn to gentamicin may depend on effective uptake of the drug, which was, in part, mediated by the TRPV1 and TRPV4 proteins.
Animals ; Cell Death/drug effects ; Cell Polarity/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Gadolinium/metabolism ; Gentamicins/*metabolism/pharmacology ; Hair Cells, Auditory/drug effects/*metabolism ; Hair Cells, Auditory, Inner/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Ruthenium Red/metabolism ; TRPV Cation Channels/*metabolism ; Time Factors ; Xanthenes/metabolism ; Zebrafish

No abstract available.
Antigens, CD34/metabolism ; Carcinoma, Hepatocellular/pathology/*radiography ; Contrast Media/chemistry/diagnostic use ; Gadolinium DTPA/chemistry/*diagnostic use ; Humans ; Immunohistochemistry ; Liver Neoplasms/pathology/*radiography ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Tomography, X-Ray Computed

Akt/protein kinase B is a well-known cell survival factor and activated by many stimuli including mechanical stretching. Therefore, we evaluated the cardioprotective effect of a brief mechanical stretching of rat hearts and determined whether activation of Akt through phosphatidylinositol 3-kinase (PI3K) is involved in stretch-induced cardioprotection (SIC). Stretch preconditioning reduced infarct size and improved post-ischemic cardiac function compared to the control group. Phosphorylation of Akt and its downstream substrate, GSK-3beta, was increased by mechanical stretching and completely blocked by wortmannin, a PI3K inhibitor. Treatment with lithium or SB216763 (GSK-3beta inhibitors) before ischemia induction mimicked the protective effects of SIC on rat heart. Gadolinium (Gd3+), a blocker of stretch-activated ion channels (SACs), inhibited the stretch-induced phosphorylation of Akt and GSK-3beta. Furthermore, SIC was abrogated by wortmannin and Gd3+. In vivo stretching induced by an aorto-caval shunt increased Akt phosphorylation and reduced myocardial infarction; these effects were diminished by wortmannin and Gd3+ pretreatment. Our results showed that mechanical stretching can provide cardioprotection against ischemia-reperfusion injury. Additionally, the activation of Akt, which might be regulated by SACs and the PI3K pathway, plays an important role in SIC.
Androstadienes/pharmacology ; Animals ; Gadolinium/pharmacology ; Glycogen Synthase Kinase 3/*metabolism ; Indoles/pharmacology ; *Ischemic Preconditioning, Myocardial ; Lithium/pharmacology ; Male ; Maleimides/pharmacology ; Myocardial Reperfusion Injury/enzymology/physiopathology/*prevention & control ; Phosphatidylinositol 3-Kinase/*antagonists & inhibitors/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/*metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Specific Pathogen-Free Organisms

This paper reports on issues relating to the optimal use of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (Gd-EOB-DTPA MR imaging) together with the generation of consensus statements from a working group meeting, which was held in Seoul, Korea (2010). Gd-EOB-DTPA has been shown to improve the detection and characterization of liver lesions, and the information provided by the hepatobiliary phase is proving particularly useful in differential diagnoses and in the characterization of small lesions (around 1-1.5 cm). Discussion also focused on advances in the role of organic anion-transporting polypeptide 8 (OATP8) transporters. Gd-EOB-DTPA is also emerging as a promising tool for functional analysis, enabling the calculation of post-surgical liver function in the remaining segments. Updates to current algorithms were also discussed.
Algorithms ; Contrast Media/*diagnostic use/metabolism ; Diagnosis, Differential ; Gadolinium DTPA/*diagnostic use/metabolism ; Humans ; Liver Diseases/*diagnosis/metabolism/surgery ; Liver Function Tests ; *Magnetic Resonance Imaging ; Organic Anion Transporters, Sodium-Independent/metabolism ; Postoperative Complications/diagnosis ; Practice Guidelines as Topic

The authors investigated objective response rate to high dose methotrexate (HDMTX)-based combination chemotherapy in primary central nervous system lymphoma (PCNSL), and sought to identify factors that influence response to HDMTX-based combination therapy. Prospective observational analysis was performed on 52 PCNSL patients. All patients received HDMTX (3.5 g/m2) and vincristine (1.4 mg/m2/day) for one day during weeks 1, 3, 5, 7, and 9, and procarbazine (100 mg/m2/day) for one week during weeks 1, 5, and 9. Forty-one patients (78.8%) achieved complete or partial remission. Higher objective response rates were observed for patients with: 1) age < 60 yr; 2) Eastern Cooperative Oncology Group (ECOG) performance score of < 2; 3) low risk status as defined by the International Extranodal Lymphoma Study Group; 4) p53 positivity; 5) XBP-1 negativity; 6) MUM-1 negativity; and 7) homogenous gadolinium enhancement in MR images. Multivariate analysis showed that ECOG performance score of < 2, low risk, negativity for XBP-1, homogenous gadolinium enhancement by MRI, and response to chemotherapy were associated with longer overall survival. In particular, it is interesting to note that patients with a PCNSL that is homogenously enhanced by gadolinium have a higher objective response rate, and a longer progression-free survival and overall survival.
Adult ; Age Factors ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Central Nervous System Neoplasms/*drug therapy/mortality ; Contrast Media/chemistry/diagnostic use ; DNA-Binding Proteins/metabolism ; Disease-Free Survival ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Gadolinium/chemistry/diagnostic use ; Humans ; Interferon Regulatory Factors/metabolism ; Lymphoma/*drug therapy/mortality ; Magnetic Resonance Imaging ; Male ; Methotrexate/*administration & dosage ; Middle Aged ; Odds Ratio ; Procarbazine/*administration & dosage ; Prospective Studies ; Recurrence ; Severity of Illness Index ; Transcription Factors/metabolism ; Tumor Suppressor Protein p53/metabolism ; Vincristine/*administration & dosage

OBJECTIVE: To evaluate whether the histopathological differentiation and the expression of vascular endothelial growth factor (VEGF) of hepatocellular carcinoma (HCC) do show correlation with the apparent diffusion coefficient (ADC) value on diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Twenty-seven HCCs from 27 patients who had undergone preoperative liver MRI (1.5T) and surgical resection were retrospectively reviewed. DWI was obtained with a single-shot, echo-planar imaging sequence in the axial plane (b values: 0 and 1,000 sec/mm2). On DWIs, the ADC value of the HCCs was measured by one radiologist, who was kept 'blinded' to the histological findings. Histopathologically, the differentiation was classified into well (n = 9), moderate (n = 9) and poor (n = 9). The expression of VEGF was semiquantitatively graded as grade 0 (n = 8), grade 1 (n = 9) and grade 2 (n = 10). We analyzed whether the histopathological differentiation and the expression of VEGF of the HCC showed correlation with the ADC value on DWI. RESULTS: The mean ADC value of the poorly-differentiated HCCs (0.9 +/- 0.13x10(-3) mm2/s) was lower than those of the well-differentiated HCCs (1.2 +/- 0.22x10(-3) mm2/s) (p = 0.031) and moderately-differentiated HCCs (1.1 +/- 0.01x10(-3) mm2/s) (p = 0.013). There was a significant correlation between the differentiation and the ADC value of the HCCs (r = -0.51, p = 0.012). The mean ADC of the HCCs with a VEGF expression grade of 0, 1 and 2 was 1.1 +/- 0.17, 1.1 +/- 0.21 and 1.1 +/- 0.18x10(-3) mm2/s, respectively. The VEGF expression did not show correlation with the ADC value of the HCCs (r = 0.07, p = 0.74). CONCLUSION: The histopathological differentiation of HCC shows inverse correlation with the ADC value. Therefore, DWI with ADC measurement may be a valuable tool for noninvasively predicting the differentiation of HCC.
Adult ; Aged ; Carcinoma, Hepatocellular/metabolism/*pathology ; Cell Differentiation ; Contrast Media/diagnostic use ; Diffusion Magnetic Resonance Imaging/*methods ; Echo-Planar Imaging/methods ; Female ; Gadolinium DTPA/diagnostic use ; Humans ; Image Enhancement/methods ; Liver/metabolism/pathology ; Liver Neoplasms/metabolism/*pathology ; Male ; Middle Aged ; Predictive Value of Tests ; Retrospective Studies ; Sensitivity and Specificity ; Severity of Illness Index ; Vascular Endothelial Growth Factor A/*metabolism

This study examined the corneal permeability of topical eye drop solutions added with various corneal penetrating accelerators and gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) by nuclear magnetic resonance imaging (MRI). Twenty-four New Zealand rabbits were randomly divided into 3 groups according to the random digits table: Gd-DTPA group, in which the rabbits received 23.45% Gd-DTPA; hyaluronic acid group, in which 23.45% Gd-DTPA plus 0.2% hyaluronic acid was administered; azone group, in which 23.45% Gd-DTPA with 0.2% azone was given. Fifty microliters of the eye drops was instilled into the conjunctive sac every 5 min, for a total of 6 applications in each group. Contrast medium signals in the cornea, anterior chamber, posterior chamber, and vitreous body were scanned successively by MRI. The morphology and cell density of the corneal endothelium were examined before and 24 h after the treatment. The results showed that the residence time of Gd-DTPA in the conjunctival sac in the hyaluronic acid and azone groups was longer than that in the Gd-DTPA group. The signals in the anterior chamber of the Gd-DTPA and hyaluronic acid groups were increased slightly, and those in the azone group strengthened sharply. The signal intensity continuously rose over 80 min before reaching plateau. The strengthening rate of signals in the anterior chamber was 19.63% in the Gd-DTPA group, 53.42% in the sodium hyaluronate group, and 226.94% in the azone group. No signal was detected in the posterior chamber or vitreous body in all the 3 groups. Corneal morphology and cell density did not show any significant changes after the treatment in all the 3 groups. It was concluded that azone can significantly improve the corneal permeability of drugs that are similar to Gd-DTPA in molecular weight and molecular size, and MRI is a noninvasive technique that can dynamically detect eye drop metabolism in real time.
Animals ; Azepines ; administration & dosage ; pharmacokinetics ; Contrast Media ; administration & dosage ; pharmacokinetics ; Cornea ; metabolism ; Female ; Gadolinium DTPA ; administration & dosage ; pharmacokinetics ; Magnetic Resonance Imaging ; Male ; Ophthalmic Solutions ; Permeability ; Rabbits

OBJECTIVE: To determine the utility of intercellular adhesion molecule (ICAM)-1 antibody-conjugated gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA-anti-ICAM-1) as a targeted contrast agent for the molecular magnetic resonance imaging (MRI) in collagen-induced arthritis (CIA). MATERIALS AND METHODS: Three groups of mice were used: non-arthritic normal, CIA mice in both the early inflammatory and chronic destructive phases. The MR images of knee joints were obtained before and after injection of Gd-DTPA-anti-ICAM-1, Gd-DTPA, and Gd-DTPA-Immunoglobulin G (Ig G) and were analyzed quantitatively. The patterns of enhancement on the MR images were compared with the histological and immunohistochemical ICAM-1 staining. RESULTS: The images obtained after injection of Gd-DTPA-anti-ICAM-1 displayed gradually increasing signal enhancement from the moment following injection (mean +/- standard deviation [SD]: 424.3 +/- 35.2, n = 3) to 24 hours (532 +/- 11.3), rather than on pre-enhanced images (293 +/- 37.6) in the early inflammatory phase of CIA mice. However, signal enhancement by Gd-DTPA and Gd-DTPA-IgG disappeared after 80 minutes and 24 hours, respectively. In addition, no significant enhancement was seen in the chronic destructive phase of CIA mice, even though they also showed inflammatory changes on T2-weighted MR images. ICAM-1 expression was demonstrated in the endothelium and proliferating synovium of the early inflammatory phase of CIA mice, but not in the chronic destructive phase. CONCLUSION: Molecular MRI with Gd-DTPA-anti-ICAM-1 displays specific images targeted to ICAM-1 that is expressed in the inflamed synovium of CIA. This novel tool may be useful for the early diagnosis and differentiation of the various stages of rheumatoid arthritis.
Animals ; Arthritis, Experimental/*metabolism ; Collagen ; Contrast Media ; Disease Models, Animal ; Gadolinium DTPA/diagnostic use ; Intercellular Adhesion Molecule-1/*metabolism ; Knee Joint/*metabolism/radiography ; Magnetic Resonance Imaging/*methods ; Male ; Mice ; Synovial Membrane/*metabolism/radiography

BACKGROUNDThe cellular plasma membrane represents a natural barrier to many exogenous molecules including magnetic resonance (MR) contrast agent. Cell penetrating peptide (CPP) is used to internalize proteins, peptides, and radionuclide. This study was undertaken to assess the value of a new intracellular MR contrast medium, CPP labeled diethylenetriamine pentaacetic acid gadolinium (Gd-DTPA) in molecular imaging in vitro.

METHODSFluorescein-5-isothiocyanate (FITC) and Gd-DTPA respectively labeled with CPP (FITC-CPP, Gd-DTPA-CPP) were synthesized by the solid-phase method. Human hepatic cancer cell line-HepG2 was respectively stained by FITC-CPP and FITC to observe the uptake and intracellular distribution. HepG2 was respectively incubated with 100 nmol/ml Gd-DTPA-CPP for 0, 10, 30, 60 minutes, and imaged by MR for studying the relationship between the incubation time and T(1)WI signal. The cytotoxicity to NIH3T3 fibroblasts cells was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide reduction assay (MTT).

RESULTSThe molecular weights of CPP labeled imaging agents, which were determined by MALDI mass spectrometry (FITC-CPP MW = 2163.34, Gd-DTPA-CPP MW = 2285.99), were similar to the calculated molecular weights. Confocal microscopy suggested HepG2 translocated FITC-CPP in cytoplasm and nucleus independent with the incubation temperature. MR images showed HepG2 uptaken Gd-DTPA-CPP had a higher T(1) weighted imaging (T(1)WI) signal, and that the T(1)WI signal intensity was increasing in a time-dependent manner (r = 0.972, P = 0.001), while the signal intensity between the cells incubated by Gd-DTPA for 60 minutes and the controlled cells was not significantly different (P = 0.225). By MTT, all concentrations from 50 nmol/ml to 200 nmol/ml had no significant (F = 0.006, P = 1.000) effect on cell viability of mouse NIH3T3 fibroblasts, compared with the control group.

CONCLUSIONSThe newly constructed CPP based on polyarginine can translocate cells by carrying FITC and MR contrast agent Gd-DTPA, and the intracellular concentrations are readily detectable by MR imaging, suggesting a new way for MR molecular imaging.

Cell Line, Tumor ; Cell Membrane Permeability ; Contrast Media ; Fluorescein-5-isothiocyanate ; Gadolinium DTPA ; Humans ; Magnetic Resonance Imaging ; methods ; Peptides ; metabolism