Anti-Inflammatory Actions of Expectorants in a Rat Carrageenan-Induced Footpad Edema Model.

S-Carboxymethyl-L-cysteine (SCMS) exhibits sputum-regulating and anti-inflammatory actions. Previous studies reported the anti-inflammatory effects of SCMS on chronic inflammatory diseases, but no study has examined these effects on acute inflammatory diseases. In this study, we investigated the anti-inflammatory effects of SCMS in a rat carrageenan-induced footpad edema model, which is routinely used as an acute inflammation model. Expectorants were administered to rats with footpad edema induced by subcutaneously administering 1%λ-carrageenan to the footpad of the left posterior limb, and the dose dependency of the anti-inflammatory effects was evaluated. As a result, even when the dose of SCMS was increased to 400 mg/kg, there were no inhibitory effects on edema. Furthermore, we examined the inhibitory effects of other expectorants (ambroxol hydrochloride, N-acetyl-L-cysteine, L-cysteine ethylester hydrochloride, and L-cysteine methylester hydrochloride), which were reported to exhibit anti-inflammatory effects on chronic inflammation, on edema. However, none of these expectorants inhibited edema.

Association between Malnutrition Severity and Swallowing Function in Convalescent Rehabilitation Wards: A Multi-Center Cohort Study in Malnourished Patients with Sarcopenic Dysphagia.

OBJECTIVES: To evaluate the characteristics of sarcopenic dysphagia (SD) and the prognosis of swallowing function in convalescent rehabilitation hospital patients; and to investigate the association between malnutrition severity and SD. DESIGN: A prospective, multi-center, cohort study. SETTING: We extracted registry data from the Japanese Sarcopenic Dysphagia Database, focusing on patients admitted to convalescent rehabilitation hospitals. PARTICIPANTS: A total of 207 participants were recruited and stratified according to the presence or absence of SD. Next, the participants were divided into groups based on nutrition status using the Global Leadership Initiative on Malnutrition criteria: normal nutrition, moderate malnutrition, and severe malnutrition. We also compared the outcomes between patients with SD (SD group) and those without SD (no-SD group) according to malnutrition status. MEASUREMENTS: The Food Intake LEVEL Scale (FILS) score was the outcome measure. Higher scores on the FILS indicate better swallowing function. We compared the patient characteristics between the SD and non-SD groups among all patients and then according to the severity of malnutrition. RESULTS: A total of 207 patients were recruited. 11 were diagnosed with normal nutrition, 72 with moderate malnutrition, and 124 with severe malnutrition. There were 128 participants with SD and 79 participants without SD; the prevalence of SD was 61.8%. Hip fracture was the most common disease among the SD patients (34.4%). The median time to the end of follow-up was 73.5 days for the SD group and 84.0 days for the no-SD group. There was no significant difference in the FILS score between the SD and no-SD groups, but the increase in the FILS score was significantly lower in the SD group than the no-SD group among patients with severe malnutrition after adjusting for confounding factors (age, sex, FILS at admission, BMI, cognitive functional independence measure, and care level before onset) (ß = -0.206, p = 0.011, 95% confidence interval = -0.723, -0.098). CONCLUSION: Orthopedic diseases are the most common type of disease among SD patients in convalescent rehabilitation hospitals. Swallowing dysfunction was particularly severe in malnourished patients with SD. This result suggests the importance of the definition of SD for malnourished patients. We should practice nutritional management as soon as possible in severely malnourished patients diagnosed with SD.

Switching of band inversion and topological surface states by charge density wave.

Topologically nontrivial materials host protected edge states associated with the bulk band inversion through the bulk-edge correspondence. Manipulating such edge states is highly desired for developing new functions and devices practically using their dissipation-less nature and spin-momentum locking. Here we introduce a transition-metal dichalcogenide VTe2, that hosts a charge density wave (CDW) coupled with the band inversion involving V3d and Te5p orbitals. Spin- and angle-resolved photoemission spectroscopy with first-principles calculations reveal the huge anisotropic modification of the bulk electronic structure by the CDW formation, accompanying the selective disappearance of Dirac-type spin-polarized topological surface states that exist in the normal state. Thorough three dimensional investigation of bulk states indicates that the corresponding band inversion at the Brillouin zone boundary dissolves upon the CDW formation, by transforming into anomalous flat bands. Our finding provides a new insight to the topological manipulation of matters by utilizing CDWs' flexible characters to external stimuli.

Radial Spin Texture in Elemental Tellurium with Chiral Crystal Structure.

The chiral crystal is characterized by a lack of mirror symmetry and inversion center, resulting in the inequivalent right- and left-handed structures. In the noncentrosymmetric crystal structure, the spin and momentum of electrons are expected to be locked in the reciprocal space with the help of the spin-orbit interaction. To reveal the spin textures of chiral crystals, we investigate the spin and electronic structure in a p-type semiconductor, elemental tellurium, with the simplest chiral structure by using spin- and angle-resolved photoemission spectroscopy. Our data demonstrate that the highest valence band crossing the Fermi level has a spin component parallel to the electron momentum around the Brillouin zone corners. Significantly, we have also confirmed that the spin polarization is reversed in the crystal with the opposite chirality. The results indicate that the spin textures of the right- and left-handed chiral crystals are hedgehoglike, leading to unconventional magnetoelectric effects and nonreciprocal phenomena.

Effect of obesity on sperm retrieval outcome and reproductive hormone levels in Japanese azoospermic men with and without Klinefelter syndrome.

Obesity is reported to have adverse effects on semen quality and the endocrine system. In this study, we evaluated the effect of obesity on sperm retrieval outcome and reproductive hormone levels in Japanese men with non-obstructive azoospermia (NOA). This study is based on the clinical records of 217 men [172 with a 46,XY karyotype, 45 with Klinefelter syndrome (KS)] with NOA who underwent microdissection testicular sperm extraction at Nagoya City University Hospital between January 2004 and December 2014. Body mass index (BMI) and serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and total testosterone (TT) were measured in all patients. In a subset of patients, bioavailable testosterone (cBAT) also was calculated. Values were evaluated separately in patients with and without KS. Sperm retrieval rates (SRRs) in 46,XY men with a BMI <25 kg/m2 and ≥25 kg/m2 were 29.3% and 18.4%, respectively (p = 0.142), while SRRs in KS men with a BMI <25 kg/m2 and ≥25 kg/m2 were 25.0% and 35.3%, respectively (p = 0.460). TT level in men with a BMI ≥25 kg/m2 was lower than that in men with a BMI <25 kg/m2 , regardless of KS status. According to Pearson product-moment correlation coefficients, TT and cBAT levels tended to have negative correlations with BMI; however, statistical significance was observed only for TT level in 46,XY men (r = 0.340, p < 0.001). LH and FSH levels were negatively correlated with BMI in KS men (r = -0.466, p = 0.001 and r = -0.647, p < 0.001, respectively), but not in 46,XY men. These results suggest that obesity may be irrelevant to sperm retrieval outcome in patients with NOA. The negative correlations between gonadotropins and BMI in patients with KS suggest an underlying suppressive effect on gonadotropin excretion, which is distinctive in obese patients with KS.

Volumetric CT with sparse detector arrays (and application to Si-strip photon counters).

Novel x-ray medical imaging sensors, such as photon counting detectors (PCDs) and large area CCD and CMOS cameras can involve irregular and/or sparse sampling of the detector plane. Application of such detectors to CT involves undersampling that is markedly different from the commonly considered case of sparse angular sampling. This work investigates volumetric sampling in CT systems incorporating sparsely sampled detectors with axial and helical scan orbits and evaluates performance of model-based image reconstruction (MBIR) with spatially varying regularization in mitigating artifacts due to sparse detector sampling. Volumetric metrics of sampling density and uniformity were introduced. Penalized-likelihood MBIR with a spatially varying penalty that homogenized resolution by accounting for variations in local sampling density (i.e. detector gaps) was evaluated. The proposed methodology was tested in simulations and on an imaging bench based on a Si-strip PCD (total area 5 cm × 25 cm) consisting of an arrangement of line sensors separated by gaps of up to 2.5 mm. The bench was equipped with translation/rotation stages allowing a variety of scanning trajectories, ranging from a simple axial acquisition to helical scans with variable pitch. Statistical (spherical clutter) and anthropomorphic (hand) phantoms were considered. Image quality was compared to that obtained with a conventional uniform penalty in terms of structural similarity index (SSIM), image uniformity, spatial resolution, contrast, and noise. Scan trajectories with intermediate helical width (~10 mm longitudinal distance per 360° rotation) demonstrated optimal tradeoff between the average sampling density and the homogeneity of sampling throughout the volume. For a scan trajectory with 10.8 mm helical width, the spatially varying penalty resulted in significant visual reduction of sampling artifacts, confirmed by a 10% reduction in minimum SSIM (from 0.88 to 0.8) and a 40% reduction in the dispersion of SSIM in the volume compared to the constant penalty (both penalties applied at optimal regularization strength). Images of the spherical clutter and wrist phantoms confirmed the advantages of the spatially varying penalty, showing a 25% improvement in image uniformity and 1.8 × higher CNR (at matched spatial resolution) compared to the constant penalty. The studies elucidate the relationship between sampling in the detector plane, acquisition orbit, sampling of the reconstructed volume, and the resulting image quality. They also demonstrate the benefit of spatially varying regularization in MBIR for scenarios with irregular sampling patterns. Such findings are important and integral to the incorporation of a sparsely sampled Si-strip PCD in CT imaging.

Circulating microparticles from diabetic rats impair endothelial function and regulate endothelial protein expression.

AIM: Diabetes mellitus increases the risk of cardiovascular disease, which is accompanied by functional and structural changes in the vascular system. Microparticles (MPs) have been described as biological vectors of endothelial dysfunction in other pathologies. However, the molecular mechanisms underlying their formation and signalling are unclear. We investigated the role of MPs derived from streptozotocin (STZ)-induced diabetic rats in endothelial function. METHODS: Male Wistar rats were injected with STZ to induce diabetes, and MPs isolated from control or STZ-induced diabetic rats were characterized by dot blotting (assessed by CD62P detections), flow cytometry (assessed by annexin V detections) and ELISA. Carotid arteries from rats were incubated with MPs, and expressions of enzymes and endothelium-dependent relaxation were analysed. RESULTS: The circulating levels of MPs, particularly the levels of platelet-derived microparticles, from diabetic rats were higher than those present in controls. Endothelium-dependent relaxation induced by acetylcholine (ACh) was attenuated in carotid arteries from STZ-induced diabetic rats. Following the incubation of control carotid arteries with MPs isolated from STZ rats, ACh-induced endothelium-dependent relaxation was impaired, but MPs isolated from control rats had no such effect. Furthermore, the effect of MPs was mediated by a decrease in expression of endothelial nitric oxide synthase (eNOS) and the overexpression of caveolin-1. CONCLUSION: Circulating MPs isolated from STZ-induced diabetic rats induce endothelial dysfunction in carotid arteries and regulate protein expressions of eNOS and caveolin-1. These data advance our understanding of the deleterious effects of circulating MPs observed in disorders with diabetic complications.

Establishment of a model of acetaminophen-induced hepatotoxicity in different weekly-aged ICR mice.

Acetaminophen (APAP), a widely used analgesic and antipyretic drug, has the potential to cause lethal hepatotoxicity. Mice are widely used for developing murine models of APAP-induced hepatotoxicity, and many researchers have used these models for APAP-related studies including the fields of biology, pharmacology and toxicology. Although drug-induced hepatotoxicity is dependent on a number of factors (species, gender and age), very few studies have investigated the effect of aging on APAP hepatotoxicity. In this study, we evaluated the effect of age on APAP-induced hepatotoxicity in different weekly-aged mice to establish a model of APAP-induced hepatotoxicity that is an accurate reflection of general experimental conditions. Male ICR mice 4, 6, 8, 10 and 12 weeks old were given APAP intraperitoneally, and mortality, hepatic damage and the plasma concentration of APAP metabolites were evaluated. It was found that younger male ICR mice were relatively resistant to hepatotoxicity induced by intraperitoneal APAP administration. In addition, the APAP-glucuronide concentration in plasma remained essentially the same among the differently-aged mice, while APAP-sulfate levels were dramatically decreased in an age-dependent manner. Thus, it is recommended that mice of the same ages be used in studies related to APAP-induced hepatotoxixity. These results provide evidence in support of not only the age-related changes in susceptibility to APAP-derived hepatotoxicity in mice but also in developing mouse models for APAP-related studies.

A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L.

BACKGROUND: Thymic carcinoma (TC) is an exceptionally rare tumor, which has a very poor prognosis differing from thymoma. Till date, there has been no report of any results of clinical trials focusing on TC. The role of non-anthracycline-based chemotherapy has not been elucidated since the previous studies included a relatively small number of TC patients. This single-arm study evaluated carboplatin and paclitaxel (CbP) in chemotherapy-naive patients with advanced TC. PATIENTS AND METHODS: The study treatment consisted of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) every 3 weeks for a maximum of six cycles. The primary end point was objective response rate (ORR) by independent review. The secondary end points included overall survival (OS), progression-free survival (PFS), and safety. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05. RESULTS: Forty patients from 21 centers were enrolled for this study from May 2008 to November 2010. Of the 39 patients evaluable for analysis, 36 were pathologically diagnosed by independent review, and 97% patients were eventually TC. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval 21%-53%; P = 0.031). The median PFS was 7.5 (6.2-12.3) months, while OS did not reach the median value. Major adverse event was grade 3-4 neutropenia in 34 patients (87%). There was no treatment-related death. CONCLUSIONS: In this largest trial with TC, CbP showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, which is the current standard treatment of thymic neoplasm. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.

Spectral CT of the Extremities with a Silicon Strip Photon Counting Detector.

PURPOSE: Photon counting x-ray detectors (PCXDs) are an important emerging technology for spectral imaging and material differentiation with numerous potential applications in diagnostic imaging. We report development of a Si-strip PCXD system originally developed for mammography with potential application to spectral CT of musculoskeletal extremities, including challenges associated with sparse sampling, spectral calibration, and optimization for higher energy x-ray beams. METHODS: A bench-top CT system was developed incorporating a Si-strip PCXD, fixed anode x-ray source, and rotational and translational motions to execute complex acquisition trajectories. Trajectories involving rotation and translation combined with iterative reconstruction were investigated, including single and multiple axial scans and longitudinal helical scans. The system was calibrated to provide accurate spectral separation in dual-energy three-material decomposition of soft-tissue, bone, and iodine. Image quality and decomposition accuracy were assessed in experiments using a phantom with pairs of bone and iodine inserts (3, 5, 15 and 20 mm) and an anthropomorphic wrist. RESULTS: The designed trajectories improved the sampling distribution from 56% minimum sampling of voxels to 75%. Use of iterative reconstruction (viz., penalized likelihood with edge preserving regularization) in combination with such trajectories resulted in a very low level of artifacts in images of the wrist. For large bone or iodine inserts (>5 mm diameter), the error in the estimated material concentration was <16% for (50 mg/mL) bone and <8% for (5 mg/mL) iodine with strong regularization. For smaller inserts, errors of 20-40% were observed and motivate improved methods for spectral calibration and optimization of the edge-preserving regularizer. CONCLUSION: Use of PCXDs for three-material decomposition in joint imaging proved feasible through a combination of rotation-translation acquisition trajectories and iterative reconstruction with optimized regularization.

Cascaded systems analysis of photon counting detectors.

PURPOSE: Photon counting detectors (PCDs) are an emerging technology with applications in spectral and low-dose radiographic and tomographic imaging. This paper develops an analytical model of PCD imaging performance, including the system gain, modulation transfer function (MTF), noise-power spectrum (NPS), and detective quantum efficiency (DQE). METHODS: A cascaded systems analysis model describing the propagation of quanta through the imaging chain was developed. The model was validated in comparison to the physical performance of a silicon-strip PCD implemented on an experimental imaging bench. The signal response, MTF, and NPS were measured and compared to theory as a function of exposure conditions (70 kVp, 1-7 mA), detector threshold, and readout mode (i.e., the option for coincidence detection). The model sheds new light on the dependence of spatial resolution, charge sharing, and additive noise effects on threshold selection and was used to investigate the factors governing PCD performance, including the fundamental advantages and limitations of PCDs in comparison to energy-integrating detectors (EIDs) in the linear regime for which pulse pileup can be ignored. RESULTS: The detector exhibited highly linear mean signal response across the system operating range and agreed well with theoretical prediction, as did the system MTF and NPS. The DQE analyzed as a function of kilovolt (peak), exposure, detector threshold, and readout mode revealed important considerations for system optimization. The model also demonstrated the important implications of false counts from both additive electronic noise and charge sharing and highlighted the system design and operational parameters that most affect detector performance in the presence of such factors: for example, increasing the detector threshold from 0 to 100 (arbitrary units of pulse height threshold roughly equivalent to 0.5 and 6 keV energy threshold, respectively), increased the f50 (spatial-frequency at which the MTF falls to a value of 0.50) by ∼30% with corresponding improvement in DQE. The range in exposure and additive noise for which PCDs yield intrinsically higher DQE was quantified, showing performance advantages under conditions of very low-dose, high additive noise, and high fidelity rejection of coincident photons. CONCLUSIONS: The model for PCD signal and noise performance agreed with measurements of detector signal, MTF, and NPS and provided a useful basis for understanding complex dependencies in PCD imaging performance and the potential advantages (and disadvantages) in comparison to EIDs as well as an important guide to task-based optimization in developing new PCD imaging systems.

Dual-energy cone-beam CT with a flat-panel detector: effect of reconstruction algorithm on material classification.

PURPOSE: Cone-beam CT (CBCT) with a flat-panel detector (FPD) is finding application in areas such as breast and musculoskeletal imaging, where dual-energy (DE) capabilities offer potential benefit. The authors investigate the accuracy of material classification in DE CBCT using filtered backprojection (FBP) and penalized likelihood (PL) reconstruction and optimize contrast-enhanced DE CBCT of the joints as a function of dose, material concentration, and detail size. METHODS: Phantoms consisting of a 15 cm diameter water cylinder with solid calcium inserts (50-200 mg/ml, 3-28.4 mm diameter) and solid iodine inserts (2-10 mg/ml, 3-28.4 mm diameter), as well as a cadaveric knee with intra-articular injection of iodine were imaged on a CBCT bench with a Varian 4343 FPD. The low energy (LE) beam was 70 kVp (+0.2 mm Cu), and the high energy (HE) beam was 120 kVp (+0.2 mm Cu, +0.5 mm Ag). Total dose (LE+HE) was varied from 3.1 to 15.6 mGy with equal dose allocation. Image-based DE classification involved a nearest distance classifier in the space of LE versus HE attenuation values. Recognizing the differences in noise between LE and HE beams, the LE and HE data were differentially filtered (in FBP) or regularized (in PL). Both a quadratic (PLQ) and a total-variation penalty (PLTV) were investigated for PL. The performance of DE CBCT material discrimination was quantified in terms of voxelwise specificity, sensitivity, and accuracy. RESULTS: Noise in the HE image was primarily responsible for classification errors within the contrast inserts, whereas noise in the LE image mainly influenced classification in the surrounding water. For inserts of diameter 28.4 mm, DE CBCT reconstructions were optimized to maximize the total combined accuracy across the range of calcium and iodine concentrations, yielding values of ∼ 88% for FBP and PLQ, and ∼ 95% for PLTV at 3.1 mGy total dose, increasing to ∼ 95% for FBP and PLQ, and ∼ 98% for PLTV at 15.6 mGy total dose. For a fixed iodine concentration of 5 mg/ml and reconstructions maximizing overall accuracy across the range of insert diameters, the minimum diameter classified with accuracy >80% was ∼ 15 mm for FBP and PLQ and ∼ 10 mm for PLTV, improving to ∼ 7 mm for FBP and PLQ and ∼ 3 mm for PLTV at 15.6 mGy. The results indicate similar performance for FBP and PLQ and showed improved classification accuracy with edge-preserving PLTV. A slight preference for increased smoothing of the HE data was found. DE CBCT discrimination of iodine and bone in the knee was demonstrated with FBP and PLTV at 6.2 mGy total dose. CONCLUSIONS: For iodine concentrations >5 mg/ml and detail size ∼ 20 mm, material classification accuracy of >90% was achieved in DE CBCT with both FBP and PL at total doses <10 mGy. Optimal performance was attained by selection of reconstruction parameters based on the differences in noise between HE and LE data, typically favoring stronger smoothing of the HE data, and by using penalties matched to the imaging task (e.g., edge-preserving PLTV in areas of uniform enhancement).

A biological phantom for evaluation of CT image reconstruction algorithms.

In recent years, iterative algorithms have become popular in diagnostic CT imaging to reduce noise or radiation dose to the patient. The non-linear nature of these algorithms leads to non-linearities in the imaging chain. However, the methods to assess the performance of CT imaging systems were developed assuming the linear process of filtered backprojection (FBP). Those methods may not be suitable any longer when applied to non-linear systems. In order to evaluate the imaging performance, a phantom is typically scanned and the image quality is measured using various indices. For reasons of practicality, cost, and durability, those phantoms often consist of simple water containers with uniform cylinder inserts. However, these phantoms do not represent the rich structure and patterns of real tissue accurately. As a result, the measured image quality or detectability performance for lesions may not reflect the performance on clinical images. The discrepancy between estimated and real performance may be even larger for iterative methods which sometimes produce "plastic-like", patchy images with homogeneous patterns. Consequently, more realistic phantoms should be used to assess the performance of iterative algorithms. We designed and constructed a biological phantom consisting of porcine organs and tissue that models a human abdomen, including liver lesions. We scanned the phantom on a clinical CT scanner and compared basic image quality indices between filtered backprojection and an iterative reconstruction algorithm.

Noise Reduction in Material Decomposition for Low-Dose Dual-Energy Cone-Beam CT.

PURPOSE: Dual-energy cone-beam CT (DE-CBCT) is an emerging technology with potential application in diagnostic imaging and image-guided interventions. This paper reports DE-CBCT feasibility and investigates decomposition algorithms for maximizing low-dose performance for reconstruction-based DE decomposition. A framework of binary decision theory is used to examine the accuracy of DE decompositions obtained from analytical reconstructions of differentially filtered low-energy (LE) and high-energy (HE) data and from penalized likelihood (PL) reconstructions with differential regularization using quadratic and total variation penalties. METHODS: Accurate DE-CBCT decomposition benefits from consideration of all system noise components. Filtered backprojection (FBP) reconstruction-based decomposition was investigated with differential filtering of LE and HE data. Penalized likelihood reconstruction-based decomposition with differential regularization was hypothesized to further improve low-dose performance, especially when coupled with regularization through a total variation edge preserving penalty that encourages piecewise smooth images. Performance of decomposition was assessed in terms of a binary hypothesis framework of sensitivity, specificity, and accuracy. Studies involved experiments on a DE-CBCT testbench, phantoms of variable material type and concentration, and cadavers (knee arthrography). RESULTS: Studies support the overall feasibility of accurate, low-dose DE-CBCT at concentration down to 5 mg/ml (iodine), dose ~3-6 mGy, and accuracy of material classification ~90%. Reconstruction-based decomposition with quadratic PL performed comparably to FBP. PL with a total variation penalty provided edge preservation and piecewise smooth images that aided DE classification and achieved improved performance over FBP and quadratic PL, reaching accuracy of ~0.98 for 2 mg/mL iodine at 3.2 mGy, compared to approx. 0.9 for FBP and quadratic PL. CONCLUSIONS: Accurate material decomposition with DE-CBCT is feasible at low dose and benefits from a rigorous assessment of noise mechanisms among various reconstruction-based techniques. The work points to the potential for non-linear iterative reconstruction methods for high-quality decomposition at low material concentration and dose.

Suppressed G-protein-coupled receptor kinase 2 activity protects female diabetic-mouse aorta against endothelial dysfunction.

AIM: Pre-menopausal women have less cardiovascular disease and lower cardiovascular morbidity and mortality than men the same age. Previously, we noted in mice that G-protein-coupled receptor kinase 2 (GRK2) negatively regulates the Akt/eNOS pathway in male diabetic aortas and that endothelial function via the Akt/eNOS pathway is less affected in female diabetic aortas. The cellular mechanisms underlying these sex differences remain unclear. We aimed to investigate the ways in which GRK2 might modulate vascular functions in male and female diabetic mice (DM). METHODS: Vascular functions were examined in aortic rings. GRK2, ß-arrestin 2 and Akt/eNOS-signalling-pathway protein levels and activities were assayed by Western blotting. RESULTS: Phenylephrine-induced contraction was greater, while both clonidine-induced and insulin-induced relaxations were weaker (vs. male controls), in aortas from male type 2 DM, suggesting impairments of the Akt/eNOS pathway and α-adrenoceptor function. GRK2-inhibitor reversed only the impairment in Akt/eNOS-pathway-mediated relaxation in male DM. Increases in GRK2 activity, GRK2 expression in the membrane, plasma Ang II and systolic blood pressure were seen in male DM (vs. male controls) but not in female DM; these increases were attenuated by GRK2-inhibitor treatment. Repeatedly obtaining clonidine concentration-response curves led to reduced relaxation in male and in female DM aortas, indicating similar desensitization between female DM and male DM. This effect was reversed by GRK2-inhibitor in both sexes. CONCLUSION: GRK2 plays a key role in modulating the aortic vasodilator effect of clonidine by selectively affecting the Akt/eNOS pathway. This action of GRK2 is more powerful in male than in female DM.

Mechanisms underlying reduced P2Y(1) -receptor-mediated relaxation in superior mesenteric arteries from long-term streptozotocin-induced diabetic rats.

AIM: Extracellular nucleotides activate cell-surface purinergic (P2) receptors, contribute to the local regulation of vascular tone and play important roles in pathophysiological states. However, little is known about the vasodilator effects of P2Y(1) -receptor activation in diabetic states. We hypothesized that in a model of established type 1 diabetes, long-term streptozotocin (STZ)-induced diabetic rats, the arterial relaxation elicited by a P2Y(1) -receptor agonist would be impaired. METHODS: Relaxations to adenosine 5'-diphosphate sodium salt (ADP), 2-MeSADP (selective P2Y(1) -receptor agonist) and adenosine 5'-triphosphate disodium salt (ATP) were examined in superior mesenteric artery rings from long-term STZ-induced diabetic rats (at 50-57 weeks after STZ injection). ADP-stimulated nitric oxide (NO) production in the superior mesenteric artery was assessed by measuring the levels of NO metabolites. Mesenteric artery expressions of P2Y(1) receptor, and ADP-stimulated levels of phosphorylated endothelial NO synthase (eNOS) (at Ser(1177) and at Thr(495) ) and eNOS were detected by Western blotting. RESULTS: Arteries from diabetic rats exhibited (vs. those from age-matched control rats): (i) reduced ADP-induced relaxation, which was partly or completely inhibited by endothelial denudation, by NOS inhibitor treatment and by a selective P2Y(1) -receptor antagonist, (ii) reduced 2-MeSADP-induced relaxation, (iii) reduced ADP-stimulated release of NO metabolites and (iv) impaired ADP-induced stimulation of eNOS activity (as evidenced by reduced the fold increase in eNOS phosphorylation at Ser(1177) with no difference in fold increase in eNOS phosphorylation at Thr(495) ). The protein expression of P2Y(1) receptor did not differ between diabetic and control arteries. CONCLUSIONS: These results suggest that P2Y(1) -receptor-mediated vasodilatation is impaired in superior mesenteric arteries from long-term type 1 diabetic rats. This impairment is because of reduced P2Y(1) -receptor-mediated NO signalling, rather than to reduced P2Y(1) -receptor expression.

External coaptation of rostral mandibular fractures in calves.

Six cases of rostral mandibular fracture with considerable displacement were treated successfully by external coaptation. Four cases were simple and two were compound fractures. After xylazine sedation and manual reduction of the fractures, the casting tape was laminated to make a rigid splint below the mandibles and then the splint was secured using the casting tape passing the nasal bridge and cranial and/or caudal to the ears as it encircled the head. During application of the tape, a PVC pipe 25 mm in diameter was held in its jaws to keep the mouth open so that the calf could suckle. Simple rostral mandibular fractures were cured after two weeks of cast immobilisation and compound fractures after about three weeks. This method is easy and non-stressful and provided a good prognosis in the present cases.

Successful and long-lasting treatment of solar urticaria with ultraviolet A rush hardening therapy.

BACKGROUND: Solar urticaria (SU) is a photodermatosis that is thought to be caused through the effects of mast cell mediators released because of an altered chromophore, possibly a photoallergen recognized by IgE. Phototherapy for SU to induce a tolerant state appears to be most effective, but is often time consuming and provides only short-lived remission. Ultraviolet (UV) A rush hardening has been successful and less time consuming in serum factor-negative patients with SU. However, the mechanism of action and long-lasting effects of UVA rush hardening therapy remain unclear. OBJECTIVES: We aimed to evaluate whether UVA rush hardening exhibits long-lasting therapeutic effects in serum factor-positive patients with SU and to examine the action mechanism of tolerance. METHODS: Two serum factor-positive patients with SU were exposed to multiple UVA irradiations at 1-h intervals per day for 2 or 3 days. Intradermal injection of their in vitro-irradiated autologous serum or compound 48/80 and a prick test for histamine were performed before and after UVA rush hardening. RESULTS: The two serum factor-positive patients with SU benefited greatly from UVA rush hardening, as documented by a marked increase in minimal wealing dose, and remained symptom free without using sunscreen in their daily life. Intradermal injection of in vitro-irradiated autologous serum induced wealing before hardening, but not in tolerized skin after hardening. The responses to compound 48/80 and histamine were unaltered. CONCLUSIONS: UVA rush hardening is an effective and long-lasting treatment even in serum factor-positive patients with SU. The mechanism of tolerance may involve continued blockade of photoallergen binding to IgE on mast cells, rather than depletion of mast cell mediators or histamine tachyphylaxis.

Pravastatin normalizes endothelium-derived contracting factor-mediated response via suppression of Rho-kinase signalling in mesenteric artery from aged type 2 diabetic rat.

AIM: Although pravastatin has known pleiotropic effects against adverse cardiovascular conditions, little is known about its effects on endothelium-derived contracting factor (EDCF)-mediated signalling. We aimed to determine the effects of pravastatin on the production of and responses to EDCF in superior mesenteric arteries isolated from rats at the chronic stage of type 2 diabetes. METHODS: Contractions to acetylcholine (ACh) were examined in superior mesenteric artery rings from aged type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats (56-60 weeks old), from control age-matched non-diabetic Long-Evans Tokushima Otsuka (LETO) rats and from pravastatin-treated (10 mg kg(-1) , p.o., daily for 4 weeks) OLETF rats. Mesenteric artery expressions of cyclo-oxygenases (COXs), microsomal-PGE synthases (mPGESs), RhoA and Rho-kinase proteins, and also the level of phosphorylated ezrin, radixin and moesin (PERM), a substrate for Rho-kinase, were detected by Western blotting. RESULTS: Arteries from OLETF rats exhibited (vs. LETO rats) (1) enhanced ACh-induced EDCF-mediated contractions, which were inhibited by the Rho-kinase inhibitor Y27632, (2) reductions in the ACh-stimulated release of both PGE(2) and superoxide and (3) increased COX-1 and PERM protein expressions. Mesenteric arteries from OLETF rats treated with pravastatin exhibited (vs. untreated OLETF) (1) reduced ACh-induced contraction, (2) suppressed ACh-induced PGE(2) production and superoxide generation and (3) reduced ACh-induced PERM protein expression. CONCLUSIONS: These results suggest that pravastatin exerts beneficial effects against abnormal EDCF signalling by suppressing Rho-kinase and promoting antioxidant activity in the mesenteric arteries of rats at the chronic stage of type 2 diabetes.