Novel UV-B Phototherapy With a Light-Emitting Diode Device Prevents Atherosclerosis by Augmenting Regulatory T-Cell Responses in Mice.

BACKGROUND: Ultraviolet B (UV-B) irradiation is an effective treatment for human cutaneous disorders and was shown to reduce experimental atherosclerosis by attenuating immunoinflammatory responses. The aim of this study was to clarify the effect of specific wavelengths of UV-B on atherosclerosis and the underlying mechanisms focusing on immunoinflammatory responses. METHODS AND RESULTS: Based on light-emitting diode technology, we developed novel devices that can emit 282 nm UV-B, which we do not receive from natural sunlight, 301 nm UV-B, and clinically available 312 nm UV-B. We irradiated 6-week-old male atherosclerosis-prone Apoe-/- (apolipoprotein E-deficient) mice with specific wavelengths of UV-B and evaluated atherosclerosis and immunoinflammatory responses by performing histological analysis, flow cytometry, biochemical assays, and liquid chromatography/mass spectrometry-based lipidomics. Irradiation of 282 nm UV-B but not 301 or 312 nm UV-B significantly reduced the development of aortic root atherosclerotic plaques and plaque inflammation. This atheroprotection was associated with specifically augmented immune responses of anti-inflammatory CD4+ Foxp3 (forkhead box P3)+ regulatory T cells in lymphoid tissues, whereas responses of other immune cells were not substantially affected. Analysis of various lipid mediators revealed that 282 nm UV-B markedly increased the ratio of proresolving to proinflammatory lipid mediators in the skin. CONCLUSIONS: We demonstrated that 282 nm UV-B irradiation effectively reduces aortic inflammation and the development of atherosclerosis by systemically augmenting regulatory T-cell responses and modulating the balance between proresolving and proinflammatory lipid mediators in the skin. Our findings indicate that a novel 282 nm UV-B phototherapy could be an attractive approach to treat atherosclerosis.

Evaluation of post-colostrum ingestion changes in the protein composition of peripheral blood of newborn piglets: A pilot study.

Putatively, colostral proteins are partly absorbed and transferred to blood circulation in newborn piglets, which suggests that colostrum ingestion alters the protein composition of their blood. Here, we conducted a pilot study to estimate the changes in the protein composition of piglet blood. Plasma collected from piglets pre- and post-ingestion of colostrum (PreC and PostC) was analyzed by shotgun proteomics. Proteins in colostrum were also analyzed. We identified 393 and 427 proteins in PreC and PostC plasma, respectively, and 596 colostral proteins. Whereas 202 unique proteins were identified in PostC, PreC and PostC commonly shared 225 proteins. By contrast, when compared with PreC, 54 proteins in PostC had their emPAI values increased >2-fold. Notably, using plasma samples collected from a separate experiment, the concentrations of growth differentiation factor 8 and haptoglobin were higher in PostC than in PreC, which was validated by ELISA. Approximately 60% of the uniquely identified or highly concentrated proteins in PostC were also found in colostrum, which were likely, at least partly, transferred from colostrum. The present study demonstrated that the protein composition of plasma of newborn piglets drastically changed post-colostrum ingestion, partly due to transfer of colostral proteins.

Prognostic Nutritional Index Is Superior to Neutrophil-to-lymphocyte Ratio as a Prognostic Marker in Metastatic Breast Cancer Patients Treated With Eribulin.

BACKGROUND/AIM: The prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) are prognostic markers for operable breast cancer. However, their importance in patients with metastatic breast cancer (MBC) remains unclear. This study aimed to evaluate these parameters as prognostic markers in MBC patients treated with eribulin. PATIENTS AND METHODS: A total of 60 patients with MBC treated with eribulin were included. RESULTS: Although high PNI and low NLR were correlated with better progression-free survival (PFS) and overall survival (OS), PNI had stronger impact as prognostic marker than NLR (PNI: HR=0.35, p=0.0008 for PFS and HR=0.27, p=0.0068 for OS; NLR: HR=0.71, p=0.081 for PFS and HR=0.63, p=0.14 for OS). Multivariate analysis demonstrated that PNI was an independent predictor of PFS (HR=0.30, p=0.0009). CONCLUSION: PNI could be a more reliable prognostic marker for MBC patients treated with eribulin than NLR.

Comparative efficacy and safety of tyrosine kinase inhibitors for thyroid cancer: a systematic review and meta-analysis.

The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57-81 and 19 months, 95% CI: 9-29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25-56 and 31 months, 95% CI: 19-43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.

Neoadjuvant chemotherapy-induced decrease of prognostic nutrition index predicts poor prognosis in patients with breast cancer.

BACKGROUND: The prognostic nutritional index (PNI), which is an easily calculated nutritional index, is significantly associated with patient outcomes in various solid malignancies. This study aimed to evaluate the prognostic impact of PNI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). METHODS: We reviewed patients with breast cancer who underwent NAC and a subsequent surgery for breast cancer between 2005 and 2016. PNI before and after NAC were calculated using the following formula: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count/mm3. The relationship between PNI and prognosis was retrospectively analyzed. RESULTS: In total, 191 patients were evaluated. There was no significant difference in disease-free survival (DFS) between the pre-NAC PNI high group and the pre-NAC PNI low group (cutoff: 53.1). However, PNI decreased in 181 patients (94.7%) after NAC and the mean PNI also significantly decreased after NAC from 52.6 ± 3.8 pre-NAC to 46.5 ± 4.4 post-NAC (p < 0.01). The mean ΔPNI, which was calculated as pre-NAC PNI minus post-NAC PNI, was 5.4. The high ΔPNI group showed significantly poorer DFS than the low ΔPNI group (cut off: 5.26) (p = 0.015). Moreover, high ΔPNI was an independent risk factor of DFS on multivariate analysis (p = 0.042). CONCLUSIONS: High decrease of PNI during NAC predicts poor prognosis. Thus, maintaining the nutritional status during NAC may result in better treatment outcomes in patients with breast cancer.

Case of painless thyroiditis that developed during adjuvant chemotherapy for breast cancer.

We report a case of painless thyroiditis that occurred during adjuvant chemotherapy for breast cancer. A 41-year-old woman was diagnosed with right breast cancer and underwent surgery followed by adjuvant chemotherapy, given the tumor size and relatively high ratio of Ki-67-positive cells. Three weeks after the first intravenous administration of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2), and dexamethasone (6.6 mg/body), followed by 3 days of oral dexamethasone (8 mg/day), she complained of continued palpitations. Although Graves' disease was initially suspected, she was diagnosed with painless thyroiditis because of a low free T3:free T4 ratio and low thyroid uptake of iodine. The mechanism of painless thyroiditis, in this case, remains unclear, although supposed etiologic event was the use of cytotoxic drugs (including fluorouracil) or the withdrawal of short-term steroid administration. Painless thyroiditis very rarely occurs during chemotherapy. However, we should consider painless thyroiditis when a patient undergoing cytotoxic chemotherapy for breast cancer experiences continued palpitations. The appropriate diagnosis and treatment of symptoms might avoid an unnecessary dose reduction or discontinuation of chemotherapy and, moreover, may prevent adverse effects associated with the metabolism of anticancer agents.

Cytomegalovirus colitis in a patient undergoing postoperative adjuvant chemotherapy for lung adenocarcinoma with uracil-tegafur.

When we examine a patient with symptoms of acute enteritis in the course of chemotherapy with oral fluoropyrimidines such as uracil-tegafur (often referred to as UFT), we usually suspect 5-fluorouracil-induced enterocolitis. In case of persistent clinical symptoms despite discontinuation of chemotherapy, cytomegalovirus colitis should be considered in the differential diagnosis of chemotherapy-induced enterocolitis. We herein report the case of a patient who underwent surgery for lung adenocarcinoma followed by postoperative adjuvant chemotherapy with uracil-tegafur and was diagnosed as having cytomegalovirus colitis during the therapy. In the course of chemotherapy, cytomegalovirus colitis occasionally occurs even though the patient does not experience severe myelosuppression; thus, it is necessary that we recognize its potential occurrence.

Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging.

Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

Tyrosine-kinase inhibitors to treat radioiodine-refracted, metastatic, or recurred and progressive differentiated thyroid carcinoma [Review].

Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients' quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs.

Sedative effects of inhaled essential oil components of traditional fragrance Pogostemon cablin leaves and their structure-activity relationships.

Plants rich in essential oils, such as Pogostemon cablin (P. cablin; guǎng huò xiang), have been used for aromas and as herbal medicines since ancient times because of their sedative effects. We investigated the sedative effects of hexane extract from P. cablin using locomotor activity in mice. Inhalation of P. cablin hexane extract exhibited significant sedative activity in a dose-dependent manner. In order to isolate the active constituents, the extract was fractionated and diacetone alcohol was identified as an active compound. Inhalation of diacetone alcohol significantly reduced murine locomotor activity in a dose-dependent manner, and this effect was not observed in olfaction-impaired mice. We examined the structure-activity relationship of diacetone alcohol and similar compounds. The ketone group at the two-position and number of carbons may play important roles in the sedative activity of diacetone alcohol.

[Visualization for Traditional Quality Management Techniques--Characterization Method for Spikenard of INUBUSHI SEIYAKU Established in the Edo Period].

INUBUSHI SEIYAKU, a Japanese pharmaceutical company established in 1807, manufactures KEISHIN-TAN. This is an original drug developed by the company, and consists of 14 exotic natural medicines, spikenard, oriental bezoar, musk, agarwood, etc. It has been used for adjusting the autonomic nervous system and physical conditions. We studied the original methods of the traditional quality management techniques handed down within INUBUSHI SEIYAKU in selecting the appropriate spikenard (Nardostachys chinensis) for medicinal use. Currently, spikenards are mainly used as incense rather than medicine. KEISHIN-TAN is a rare case in that the bulk powder of the spikenards is used for pharmaceutical products in Japan. We examined the morphological characteristics and made an analysis of the component of spikenards selected by traditional methods. The raw material of the spikenards was purchased from the Japanese market, and was classified into two categories-superior, fit for medicinal use and defective, to be discarded-by traditional methods of INUBUSHI SEIYAKU. The methods of the characterization of the spikenard by INUBUSHI SEIYAKU were investigated. As a result, only thick spikenard roots over 2.0 cm in length and approximately 0.5 cm in diameter were found to be used, and the total weight of the superior was only 15% of the raw material. By comparing the weights of hexane extracts and GC-MS analyses, the content of calarene--main sedative compound in spikenards--in the superior material was 2.8 times higher than the raw material and 4.3 times higher than the defective material. The ways to devise how to enhance the pharmacological effects of spikenards may be contained in this method. These results revealed the traditional spikenard selection criteria, and may show the indications of using spikenard or its compounds for medicinal purposes.

The sedative effect of inhaled terpinolene in mice and its structure-activity relationships.

Terpinolene is a cyclic monoterpene compound found in some Labiatae herbs. In our previous study, we evaluated the sedative effect of inhaled essential oils of Microtoena patchoulii leaves in mice and isolated terpinolene as an active ingredient. We investigated the structure-activity relationships of terpinolene to identify the structural part essential to its sedative effect. Comparison of terpinolene analog activities showed that a double bond in the side-chain or pi bonds in the six-membered ring play important roles in the sedative effect. In another experiment using olfactory impaired mice, we further revealed that inhaled terpinolene exerted the effect after nasal absorption into the body.

Sedative effects of vapor inhalation of the essential oil of Microtoena patchoulii and its related compounds.

Microtoena patchoulii (Labiatae) is a perennial herb that grows in southern China. In the present study, the sedative activity of the essential oil of the leaves was evaluated using mice when the volatile oil was administered by inhalation. The inhalation of the oil by mice significantly reduced the spontaneous motor activity. Fractionation of the oil revealed that the main constituents in the oil were 1-octen-3-ol, terpinolene, patchouli alcohol, and methyl salicylate. Each 1-octen-3-ol, terpinolene, or patchouli alcohol significantly reduce the locomotor activity when it was administered singly. However, the essential oil fraction containing both patchouli alcohol and methyl salicylate did not exhibit any effects. It is suggested that methyl salicylate might negate the sedative effect of patchouli alcohol, and that the concentration ratios of the compounds in vapor would play important roles as sedatives. In order to clarify the mechanism of action, the effects of these compounds on caffeine-induced excitation and pentobarbital-induced elongation of sleeping time in mice were tested. Each 1-octen-3-ol or terpinolene reduced the locomotor activity excited by caffeine to those of normal levels. Elongation of sleeping time induced by pentobarbital was further elongated by the inhalation of terpinolene, but not by that of 1-octen-3-ol. It is indicated that terpinolene is a potent suppressor of the central nervous system.

Ocular vestibular-evoked myogenic potentials (oVEMPs) require extraocular muscles but not facial or cochlear nerve activity.

OBJECTIVES: Cervical vestibular evoked myogenic potentials (cVEMPs) have been found to be useful for clinical testing of vestibular function. Recently, investigators showed that short-latency, initially negative surface EMG potentials can be recorded around the extraocular muscles (oVEMPs) in response to air-conducted sound (ACS), bone-conducted vibration (BCV), and head taps. Although these evoked potentials, which are located around the eyes, most likely originate primarily from the otolith-ocular pathway, the possibility of contamination by other nerve activities cannot be completely eliminated. The purpose of the present study was to clarify the origin of oVEMPs by examining these possibilities using clinical findings. METHODS: Twelve healthy subjects and 15 patients were enrolled. Of the 15 patients, 3 patients had undergone exenteration of the unilateral intraorbital contents, one had undergone exenteration of the right eyeball with preservation of extraocular muscles, 5 had facial palsy, and 6 had profound hearing loss. ACS and/or BCV were used in these subjects. RESULTS: Exenteration of the unilateral intraorbital contents resulted in absence of myogenic potentials on the affected side. On the other hand, exenteration of the eyeball with preservation of extraocular muscles did not have a major impact on the responses. There were no significant differences in the waveforms between healthy subjects and patients with facial palsy or profound hearing loss. CONCLUSIONS: The results suggested that short-latency, initially negative evoked potentials recorded below the eyes are not affected by cochlear or facial nerve activities and are dependent on the presence of extraocular muscles. SIGNIFICANCE: This study provides the evidence that oVEMPs originate from exraocular muscles activated through the vestibulo-ocular pathway.

Effect of head position on vestibular evoked myogenic potentials with toneburst stimuli.

CONCLUSION: The present study demonstrated the robustness of VEMP testing with toneburst stimuli, since it is hardly affected by head position, i.e. base or tonic excitation levels of the saccule and inferior vestibular nerve. However, the small but highly significant difference found in latency should not be neglected: the gravitational axis in the upright position may have some special effect on tonic excitation of the saccule. OBJECTIVES: To evaluate the effect of head positions on vestibular evoked myogenic potentials (VEMPs) with toneburst stimuli. MATERIALS AND METHODS: VEMPs were recorded with short tonebursts of 500 Hz in 14 normal subjects in 5 head positions (upright, nose up, ear up, nose down, and ear down). The three parameters analyzed were: 1) latency of p13, 2) latency of n23, and 3) corrected amplitude of p13-n23 (CA p13-n23). RESULTS: One-way repeated measures ANOVA showed significant effects on both p13 (p=0.0245) and n23 (p<0.0001) latencies, but not on CA p13-n23. Bonferroni's post hoc test demonstrated that there were significant differences in n23 latency between the upright position and all other head positions leaning on the bed.

Cortical activation shortly after cochlear implantation.

We evaluated the cortical activations in postlingually deaf cochlear implant (CI) users in the early period (0-2 months) of CI usage. The subjects were 8 early CI users and 8 normal subjects. With tone burst stimuli (1 kHz) delivered to the right side, strong and broad activation of the ipsilateral (right) primary auditory cortex with 2 peaks and weaker activation of the contralateral (left) temporal lobe were observed in early CI users, in a clear contrast with the normal subjects in whom activation was observed in a small area of the contralateral (left) primary cortex. With word stimuli, activation of the superior frontomedian cortex presumably including the supplementary motor area and the neighboring cingulate gyri was observed in early CI users, which was absent in normal subjects. The activation in the immediate association cortices near the primary area was lower in early CI users, while the periphery of the association cortex seemed to be more mobilized.