In vivo evaluation of a monodisperse solid-in-oil-in-water miriplatin/ lipiodol emulsion in transcatheter arterial chemoembolization using a rabbit VX2 tumor model.

Transcatheter arterial chemoembolization (TACE) is a standard treatment for unresectable hepatocellular carcinoma; however, it does not always result in tumor control. Nevertheless, treatment outcome can be improved with monodisperse emulsions of anticancer agents. In this study, the distribution of a monodisperse miriplatin-Lipiodol emulsion in the tumor and its safety were evaluated in ten Japanese white rabbits. VX2 tumor was implanted into the left liver lobe. The animals were divided into control and experimental groups (of five animals each) and respectively administered a conventional miriplatin suspension or the emulsion via the left hepatic artery. Computed tomography (CT) was performed before, immediately after, and two days following TACE. All rabbits were sacrificed two days after the procedure. Each tumor was removed and cut in half for assessment of iodine concentration in one half by mass spectroscopy and evaluation of Lipiodol accumulation and adverse events in the other half. Mean Hounsfield unit (HU) values were measured using plain CT images taken before and after TACE. Iodine concentration was higher in the experimental group [1100 (750-1500) ppm, median (range)] than in the control group [840 (660-1800) ppm], although statistically not significant. Additionally, the HU value for the experimental group was higher than that for the control group immediately after [199.6 (134.0-301.7) vs. 165.3 (131.4-280.5)] and two days after [114.2 (56.1-229.8) vs. 58.3 (42.9-132.5)] TACE, although statistically not significant. Cholecystitis was observed in one rabbit in the control group. Ischemic bile duct injury was not observed in any group. The results show that Lipiodol accumulation and retention in VX2 tumor can possibly be improved with a monodisperse emulsion; however, it should be verified with a larger study. Moreover, no significant adverse events are associated with the use of the emulsion.

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats.

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

Application of oxytocin with low-level laser irradiation suppresses the facilitation of cortical excitability by partial ligation of the infraorbital nerve in rats: An optical imaging study.

The effects of current treatments for neuropathic pain are limited. Oxytocin is a novel candidate substance to relieve neuropathic pain, as demonstrated in various animal models with nerve injury. Low-level laser therapy (LLLT) is another option for the treatment of neuropathic pain. In this study, we quantified the effects of oxytocin or LLLT alone and the combination of oxytocin and LLLT on cortical excitation induced by electrical stimulation of the dental pulp using optical imaging with a voltage-sensitive dye in the neuropathic pain model with partial ligation of the infraorbital nerve (pl-ION). We applied oxytocin (OXT, 0.5 µmol) to the rat once on the day of pl-ION locally to the injured nerve. LLLT using a diode laser (810 nm, 0.1 W, 500 s, continuous mode) was performed daily via the skin to the injured nerve from the day of pl-ION to 2 days after pl-ION. Cortical responses to electrical stimulation of the mandibular molar pulp under urethane anesthesia were recorded 3 days after pl-ION. Both the amplitude and area of excitation in the primary and secondary somatosensory and insular cortices in pl-ION rats were larger than those in sham rats. The larger amplitude of cortical excitation caused by pl-ION was suppressed by OXT or LLLT. The expanded area of cortical excitation caused by pl-ION was suppressed by OXT with LLLT but not by OXT or LLLT alone. These results suggest that the combined application of OXT and LLLT is effective in relieving the neuropathic pain induced by trigeminal nerve injury.

In Vivo Antitumor Effects of MK615 Led by PD-L1 Downregulation.

BACKGROUND/AIM: MK615 extracted from Prunus mume was reported to have anti-inflammatory effects. In this article, we examined the in vivo antitumor effect of MK615 (an extract from Japanese apricot) using mouse tumor xenografts and focusing on the downregulation of PD-L1 (programmed death-ligand 1), a ligand of programmed cell death-1, a surface protein of activated T cells. MATERIALS AND METHODS: B16/BL6 melanoma cells were injected into C57BL/6 or BALB/c-nu/nu mice to establish lung metastasis. BALB/c-nu/nu mice (nude mice) were used as a T cell-deficient model. The mice were given MK615 or saline orally every other day for approximately 8 weeks, and their survival was observed. NF-κB (nuclear factor-κB) and PD-L1 expressions of metastatic lung tissues were also examined. RESULTS: The survival rate was improved only in the MK615-treated C57BL/6 mice ( P < .05), not in the saline-given control mice or BALB/c-nu/nu mice. The downregulations of NF-κB and PD-L1 were observed in both MK615-treated C57BL/6 and BALB/c-nu/nu mice. These results suggest that the antitumor effects of MK615 are associated with T cell-mediated immunity activated by MK-615-induced PD-L1 downregulation in tumor cells. CONCLUSION: MK615 is beneficial for a prolonged host survival time in the B16/BL6 melanoma xenograft model associated with T cell-mediated antitumor immunity.

Therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate-risk and high-risk prostate cancer.

OBJECTIVES: To investigate the therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate- and high-risk prostate cancer. METHODS: This was a retrospective study of 325 patients with intermediate- or high-risk prostate cancer according to the National Comprehensive Cancer Network guidelines who underwent androgen-deprivation therapy and intensity-modulated radiation therapy (76 Gy) after gold marker implantation between 2001 and 2010. RESULTS: The 5-year distant metastasis-free survival rate was significantly lower for very high-risk patients than for intermediate- and high-risk patients (82.6% vs 99.4% and 96.5%, respectively; P < 0.01). The 5-year biochemical relapse-free survival rates significantly declined with increasing prostate cancer risk (P < 0.01), and were 95.9%, 87.2%, and 73.1% for the intermediate-risk, high-risk and very high-risk patients, respectively. Acute genitourinary and gastrointestinal toxicity grade ≥3 were not observed in any of the patients. Late grade 3 genitourinary toxicity occurred in 0.3% of patients. CONCLUSION: Combination androgen-deprivation therapy and 76-Gy intensity-modulated radiation therapy with gold marker implantation offers good therapeutic outcomes with few serious complications in patients with intermediate- and high-risk prostate cancer.

Small molecules that inhibit Vif-induced degradation of APOBEC3G.

BACKGROUND: HIV-1 Vif is essential for virus replication in natural target cells such as T cells and macrophages. Vif recruits a ubiquitin ligase to degrade restrictive APOBEC3 proteins. APOBEC3G is one of the most potent retroviral restriction factors targeted by Vif and, as such, the Vif-APOBEC3G interaction has emerged as a promising HIV-1 therapeutic target. METHODS: 20,000 small molecules were used in live-cell screens for those that preserve EGFP-APOBEC3G fluorescence and luciferase-APOBEC3G luminescence in the presence of HIV-1 Vif. RESULTS: 2 compounds with similar core structures preserved APOBEC3G levels in the presence of Vif. 10 µM of compound restored APOBEC3G to levels sufficient for incorporation into vif-proficient virus particles and restriction of virus infectivity. Vif-dependent APOBEC3G polyubiquitination and general proteasomal activity were unaffected at the same concentration. CONCLUSIONS: The small molecules described here preserve APOBEC3G levels and activity in the presence of Vif. These molecules are starting points for further development as antiretrovirals.

Group cognitive-behavioral intervention for patients with burning mouth syndrome.

This study was conducted to assess the psychological characteristics of, and determine the effectiveness of group cognitive-behavioral (CB) treatment for, patients with burning mouth syndrome (BMS). The baseline characteristics of 24 female patients (age 69.7 ± 5.9 years) and an identical number of healthy female control subjects (age 69.2 ± 5.5 years) were compared. The patient group had significantly higher anxiety scores (P < 0.05) at baseline. A brief group CB intervention was delivered in a small-group format. Two sessions were planned 6 months apart. A numeric rating scale (NRS) was used to assess pain intensity. Anxiety was evaluated using a state and trait anxiety inventories. Present pain intensity decreased after both the first and second sessions. The session effect was significant (P = 0.02), but no repeat effect was found (P = 0.19). The state anxiety inventory score also decreased after the second session. The session effect was significant (P < 0.01), as was the repeat effect (P < 0.01). The trait anxiety inventory score decreased after the second session, and the session effect was significant (P = 0.013), but the repeat effect was not (P = 0.93). The results suggest that a brief group CB intervention reduces pain intensity and anxiety in patients with BMS.

Skin fragility in obese diabetic mice: possible involvement of elevated oxidative stress and upregulation of matrix metalloproteinases.

The purpose of this study was to test the hypothesis that obese diabetic mice exhibit marked skin fragility, which is caused by increased oxidative stress and increased matrix metalloproteinase (MMP) gene expression in the subcutaneous adipose tissue. Scanning electron microscopy of skin samples from Tsumura-Suzuki obese diabetic (TSOD) mice revealed thinner collagen bundles, and decreased density and convolution of the collagen fibres. Furthermore, skin tensile strength measurements confirmed that the dorsal skin of TSOD mice was more fragile to tensile force than that of non-obese mice. The mRNA expressions of heme oxygenase 1 (Hmox1), a marker of oxidative stress, Mmp2 and Mmp14 were increased in the adipose tissue of TSOD mice. Antioxidant experiments were subsequently performed to determine whether the changes in collagen fibres and skin fragility were caused by oxidative stress. Strikingly, oral administration of the antioxidant dl-α-tocopherol acetate (vitamin E) decreased Hmox1, Mmp2 and Mmp14 mRNA expressions, and improved the skin tensile strength and structure of collagen fibres in TSOD mice. These findings suggest that the skin fragility in TSOD mice is associated with dermal collagen damage and weakened tensile strength, and that oxidative stress and MMP overexpression in the subcutaneous adipose tissue may, at least in part, affect dermal fragility via a paracrine pathway. These observations may contribute to novel clinical interventions, such as dietary supplementation with antioxidants or application of skin cream containing antioxidants, which may overcome skin fragility in obese patients with diabetes.

Gustatory imagery reveals functional connectivity from the prefrontal to insular cortices traced with magnetoencephalography.

Our experience and prejudice concerning food play an important role in modulating gustatory information processing; gustatory memory stored in the central nervous system influences gustatory information arising from the peripheral nervous system. We have elucidated the mechanism of the "top-down" modulation of taste perception in humans using functional magnetic resonance imaging (fMRI) and demonstrated that gustatory imagery is mediated by the prefrontal (PFC) and insular cortices (IC). However, the temporal order of activation of these brain regions during gustatory imagery is still an open issue. To explore the source of "top-down" signals during gustatory imagery tasks, we analyzed the temporal activation patterns of activated regions in the cerebral cortex using another non-invasive brain imaging technique, magnetoencephalography (MEG). Gustatory imagery tasks were presented by words (Letter G-V) or pictures (Picture G-V) of foods/beverages, and participants were requested to recall their taste. In the Letter G-V session, 7/9 (77.8%) participants showed activation in the IC with a latency of 401.7±34.7 ms (n = 7) from the onset of word exhibition. In 5/7 (71.4%) participants who exhibited IC activation, the PFC was activated prior to the IC at a latency of 315.2±56.5 ms (n = 5), which was significantly shorter than the latency to the IC activation. In the Picture G-V session, the IC was activated in 6/9 (66.7%) participants, and only 1/9 (11.1%) participants showed activation in the PFC. There was no significant dominance between the right and left IC or PFC during gustatory imagery. These results support those from our previous fMRI study in that the Letter G-V session rather than the Picture G-V session effectively activates the PFC and IC and strengthen the hypothesis that the PFC mediates "top-down" control of retrieving gustatory information from the storage of long-term memories and in turn activates the IC.

Low dose tamsulosin for stone expulsion after extracorporeal shock wave lithotripsy: efficacy in Japanese male patients with ureteral stone.

OBJECTIVE: We evaluated the efficacy of low dose tamsulosin after extracorporeal shock wave lithotripsy (ESWL) in Japanese male patients with ureteral stone. METHODS: One hundred and two Japanese male patients with ureteral stones who underwent ESWL were randomly divided into three groups. Group A (38 patients) was given tamsulosin (0.2 mg/day); group B (30 patients) was given c horeito, a herbal medicine (7.5 g/day); and group C (34 patients) received no medication. Stone clearance was assessed at 1, 7, 14, and 28 days after ESWL using plain abdominal radiography and abdominal ultrasonography. After 28 days, stone delivery was checked every 2 weeks. RESULTS: The stone-free rate was 84.21%, 90%, and 88.24% for groups A, B, and C, respectively (P = 0.3425). The mean expulsion time was 15.66 +/- 6.14 days in group A, 27.74 +/- 25.36 days in group B, and 35.47 +/- 53.70 days in group C. The expulsion time of group A was significantly shorter than that of groups B (P = 0.0116) and C (P = 0.0424). CONCLUSIONS: The addition of tamsulosin to conservative treatment appeared to be effective in shortening the stone expulsion time.