Review of clinical studies on the nocebo effect.

Objective: To review clinical studies on the nocebo effect. PubMed was searched for relevant clinical studies as well as studies on the relationship between the nocebo effect and genes. Data sources: A total of 35 clinical studies on the nocebo effect and one study on its relationship with genes were selected for review. All were conducted outside Japan. Results and conclusion: An increasing number of clinical studies on the nocebo effect are being published. The 36 studies selected for review were grouped into the following five categories: (1) studies of how differences in participant characteristics such as personality affect susceptibility to the nocebo effect, (2) studies of how differences in provision of information about side effects affect susceptibility to the nocebo effect, (3) studies of how nocebo conditioning affects susceptibility to the nocebo effect, (4) studies of nocebo response mechanisms, and (5) studies of the nocebo effect and genetic polymorphisms. The first four categories comprised 5, 19, 8, and 3 studies, respectively, and the fifth comprised 1 study. Most of the studies investigated how differences in the provision of information affect susceptibility to the nocebo effect. Few studies investigated individual differences in the nocebo effect (differences between responders and non-responders) or mechanisms of the nocebo effect.

Effective countermeasures for Salmonella contamination in actual oilmeal-manufacturing plant in India.

AIMS: Salmonella contamination in the manufacturing process of an overseas oilmeal plant was investigated and countermeasures for Salmonella contamination were evaluated. METHODS AND RESULTS: Salmonella was detected from deposits and adhered materials inside the main processing equipment. Specifically high contamination was observed in the equipment associated with the meal cooler, with several Salmonella serovars being detected. A number of Salmonella serovars were also detected in the equipment of the fine powder recovery process. To prevent Salmonella contamination of oilmeal products, effective countermeasures that have been employed in Japan were implemented. By removing residues from the equipment and disinfecting the interior of the equipment, a significant decrease in the contamination rate of oilmeal products was achieved compared to before sanitation (P < 0·05). CONCLUSIONS: Effective countermeasures to control Salmonella contamination in the overseas manufacturing process of oilmeal were established. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report focusing on Salmonella countermeasures in an actual oilmeal-manufacturing plant overseas.

Relationship between medication adherence and glycemic control in Japanese patients with type 2 diabetes.

A cross-sectional survey of 358 patients was conducted among type 2 diabetes patients recruited at medical institutions or via an online research company. Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8). Univariate and multivariate regression analyses of glycosylated hemoglobin (HbA1c) were performed in addition to assessing demographic and disease characteristics and MMAS-8. In conclusion, medication adherence as measured by the MMAS-8 score independently contributes to altering the HbA1c level in the range of 1.12 %. The number of medications prescribed and insulin use are also related to HbA1c.

Estimation of glycaemic control in the past month using ratio of glycated albumin to HbA1c.

AIMS: To evaluate comprehensively the use of the glycated albumin to HbA1c ratio for estimation of glycaemic control in the previous month. METHODS: A total of 306 children with Type 1 diabetes mellitus underwent ≥10 simultaneous measurements of glycated albumin and HbA1c . Correlation and concordance rates were examined between HbA1c measurements taken 1 month apart (ΔHbA1c ) and glycated albumin/HbA1c ratio fluctuations were calculated as Z-scores from the cohort value at enrolment of this study cohort (method A) or the percent difference from the individual mean over time (method B). RESULTS: Fluctuations in glycated albumin/HbA1c ratio (using both methods) were weakly but significantly correlated with ΔHbA1c , whereas concordance rates were significant for glycaemic deterioration but not for glycaemic improvement. Concordance rates were higher using method B than method A. CONCLUSIONS: The glycated albumin/HbA1c ratio was able to estimate glycaemic deterioration in the previous month, while estimation of glycaemic improvement in the preceding month was limited. Because method B provided a better estimate of recent glycaemic control than method A, the individual mean of several measurements of the glycated albumin/HbA1c ratio over time may also identify individuals with high or low haemoglobin glycation phenotypes in a given population, such as Japanese children with Type 1 diabetes, thereby allowing more effective diabetes management.

Effect of serotonin transporter genotype on self-reported efficacy and activity changes of brain prefrontal area in response to placebo.

Patients benefit from drug therapy not only through pharmacological mechanisms, but also through non-pharmacological action (placebo effect), which may be mediated in part by the prefrontal area of the brain. We consider that the difference between responders and non-responders to placebo might be related to polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR). To study this idea, we performed a randomized double-blind clinical trial using caffeine and lactose (placebo). Activity in the prefrontal area of the brain was measured in terms of blood flow by means of near-infrared spectroscopy (NIRS) as an objective indicator. Self-reported feelings of drowsiness on established scales were used as subjective indicators. Twenty-one subjects in block A took caffeine on the first day and placebo on the third day, and 21 in block B took placebo on the first day and placebo on the third day. After placebo administration, improvement of sleepiness was significantly enhanced, a similar extent to that after caffeine medication. Among the 42 subjects, 22 showed S/S type polymorphism in the serotonin transporter (52.4 %), 17 showed S/L type (40.5 %) and 3 showed L/L type (7.10 %). Statistical analysis of the results indicate that subjects with L/L genotype showed a significantly greater placebo response in terms of both self-reported feeling of drowsiness and blood flow in the prefrontal area of the brain associated with working memory (46 area). Our results indicate that the L/L genotype of 5-HTTLPR, which is rare in Japanese (3.2 %) but common in Americans (32.2 %), may be associated with a greater placebo effect.

Foams stabilized with solid particles carrying stimuli-responsive polymer hairs.

Submicrometer-sized polystyrene (PS) particles carrying stimuli-responsive poly[2-(diethylamino)ethyl methacrylate] (PDEA) hairs with degrees of polymerization of 30, 60 and 90 were synthesized by dispersion polymerization and used as a particulate foam stabilizer. The effects of the composition of these PDEA-PS particles and foam formation conditions on foamability, foam stability and foam microstructures were extensively investigated. The hairy particles were found to work as an effective stabilizer of aqueous foams in basic media, in which the PDEA hairs are not protonated and thus the particle surfaces exhibit suitable wettability at the air-water interface. In contrast, little to no foam or unstable foams were formed in acidic aqueous media, in which the hairs are protonated and are therefore water soluble. Particles carrying longer hairs resulted in greater foamability and more highly stabilized foams that were capable of persisting for more than one month. Foams were found to form in a narrower pH range when using PS particles with longer hairs, due to both entropic and image charge effects. Data obtained from the touch mixer mixing method showed that both foamability and foam stability increased with increases in the concentration of polymer particles up to 10 wt%, because higher concentrations allowed greater air-water interfacial areas to be stabilized. Conversely, only minimal foam was obtained at and above 15 wt% because of the high viscosity of the resulting aqueous particle dispersion. Trials using the homogenizer mixing method showed that foam with a cream-like texture could be formed even at 40 wt% particle concentration as a result of the improved mixing efficiency. Defoamation could be induced by exposing the foams to HCl vapor. Exposure to acidic vapor led to in situ protonation of the 2-(diethylamino)ethyl methacrylate residues, rendering the PDEA hairs hydrophilic and water soluble, and desorption of the PDEA-PS particles from the air-water interface.

Functional analysis of recombinant 2-Cys peroxiredoxin from the hard tick Haemaphysalis longicornis.

Ticks are obligate haematophagous arthropods that feed on vertebrate blood containing high levels of iron. The host-derived iron reacts to oxygen in the tick's body, and then high levels of reactive oxygen species, including hydrogen peroxide (H(2)O(2)), may be generated. High levels of H(2)O(2) cause oxidative stress to aerobic organisms. Therefore, antioxidant responses are necessary to control H(2)O(2). We focused on peroxiredoxins (Prxs), H(2)O(2) -scavenging enzymes. The sequence of Haemaphysalis longicornis 2-Cys Prx (HlPrx2) was identified from fat body cDNA libraries of this tick and recombinant HlPrx2 was then prepared using Escherichia coli. By comparison with the 2-Cys Prxs of other organisms, we found two conserved cysteines in HlPrx2, Cys51 and Cys172. We examined the antioxidant activity of HlPrx2 and mutant proteins produced by a single base substitution, converting one or both of these cysteines into serines. The assays revealed that proteins containing Cys51 showed antioxidant activity when H(2)O(2) was removed. Sodium dodecyl sulphate polyacrylamide gel electrophoresis and size-exclusion chromatography demonstrated that only the wild-type HlPrx2 formed homodimers and that all of the proteins that we made had a high molecular weight peak. These results indicate that both Cys51 and Cys172 are essential for the dimerization of HlPrx2, whereas only the Cys51 residue is necessary for antioxidant activity.

Biological index of environmental lead pollution: accumulation of lead in liver and kidney in mice.

Lead (Pb) is known to be highly poisonous, and the acute poisoning of Cd causes the abdominal pains, vomiting, and shock. The digestive and nervous symptom is observed in the chronic lead poisoning. It was also known that the defect in hemoglobin synthesis by Pb produce anemia. The release of Pb into the environment presents a source of exposure for wild animals. In this study, we examined the utility of a new Pb-monitoring index in mice administered Pb. A solution containing 0.02, 0.2, 2, or 4 ppm lead chloride (PbCl2) was administered intraperitoneally to mice, and the Pb contents of the kidney and liver were determined at designated time points. The mean Pb content of both organs increased depending on the administered Pb dosage. Although the results of control was near the detection limits, the administration of 4 ppm in 4 weeks resulted in Pb levels of 260 mg ppm/wet weight and 110 ppm wet weight in the kidney and liver, respectively. However, there were no significant relationships among administered dose, duration of Pb treatment, and liver or kidney Pb content. Then, values in all mice administered control or 0.02 mg Pb were located inside the ellipse, representing the confidence area of the new index, and values in all mice administered more than 2 mg Pb were located outside the ellipse. These results confirm that animals exposed to high concentrations of Pb would be detected by this new index.

Néel-type skyrmion lattice with confined orientation in the polar magnetic semiconductor GaV4S8.

Following the early prediction of the skyrmion lattice (SkL)--a periodic array of spin vortices--it has been observed recently in various magnetic crystals mostly with chiral structure. Although non-chiral but polar crystals with Cnv symmetry were identified as ideal SkL hosts in pioneering theoretical studies, this archetype of SkL has remained experimentally unexplored. Here, we report the discovery of a SkL in the polar magnetic semiconductor GaV4S8 with rhombohedral (C3v) symmetry and easy axis anisotropy. The SkL exists over an unusually broad temperature range compared with other bulk crystals and the orientation of the vortices is not controlled by the external magnetic field, but instead confined to the magnetic easy axis. Supporting theory attributes these unique features to a new Néel-type of SkL describable as a superposition of spin cycloids in contrast to the Bloch-type SkL in chiral magnets described in terms of spin helices.

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration.

Axonal transport is critical for neuronal development and function, and defective axonal transport has been implicated in neurodegenerative diseases. However, how axonal transport is regulated, or how defective transport leads to neuronal degeneration, remains unclear. Here, we report that c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) and JNK-associated leucine zipper protein (JLP) are essential for postnatal brain development. Mice with a double-knockout (dKO) in Jsap1 and Jlp in the dorsal telencephalon developed progressive neuron loss. Using a primary neuron culture system with induced disruption of targeted genes, combined with gene rescue experiments, we show that JSAP1 and JLP regulate kinesin-1-dependent axonal transport with functional redundancy. We also show that the binding of JSAP1 and JLP to kinesin-1 heavy chain is crucial for interactions between kinesin-1 and microtubules. Furthermore, we describe a molecular mechanism by which defective kinesin-1-dependent axonal transport in Jsap1:Jlp dKO neurons causes axonal degeneration and subsequent neuronal death. JNK hyperactivation because of increased intra-axonal Ca(2+) in the Jsap1:Jlp dKO neurons was found to mediate both the axonal degeneration and neuronal death, in cooperation with the Ca(2+)-dependent protease calpain. Our results indicate that axonal JNK may relocate to the nucleus in a dynein-dependent manner, where it activates the transcription factor c-Jun, resulting in neuronal death. Taken together, our data establish JSAP1 and JLP as positive regulators of kinesin-1-dependent axonal transport, which prevents neuronal degeneration.

Effects of low-dose cyclophosphamide with piroxicam on tumour neovascularization in a canine oral malignant melanoma-xenografted mouse model.

Low-dose cyclophosphamide (CyLD) has shown promise in the treatment of several cancers; however, the effect of CyLD on canine oral malignant melanoma has never been explored. In this study, we investigated the effects of CyLD with or without piroxicam (Px) on tumour neovascularization and vascular normalization in a canine oral malignant melanoma-xenografted mice model. After treatment with CyLD, Px or a combination of both (CyPx), the growth of the tumour in the treatment groups was significantly suppressed compared to the control group at 30 days of treatment. Proliferation index was also significantly reduced by all treatments, only CyPx significantly lowered microvessel density and vascular endothelial growth factor (VEGF) levels. Additionally, CyLD significantly reduced the proportion of normal vessels and caused an imbalance between VEGF and thrombospondin-1. These results suggested that CyPx has potent anti-angiogenic effects in terms of both the number and quality of blood vessels in xenografted canine oral malignant melanoma.

Thermally driven ratchet motion of a skyrmion microcrystal and topological magnon Hall effect.

Spontaneously emergent chirality is an issue of fundamental importance across the natural sciences. It has been argued that a unidirectional (chiral) rotation of a mechanical ratchet is forbidden in thermal equilibrium, but becomes possible in systems out of equilibrium. Here we report our finding that a topologically nontrivial spin texture known as a skyrmion--a particle-like object in which spins point in all directions to wrap a sphere--constitutes such a ratchet. By means of Lorentz transmission electron microscopy we show that micrometre-sized crystals of skyrmions in thin films of Cu2OSeO3 and MnSi exhibit a unidirectional rotation motion. Our numerical simulations based on a stochastic Landau-Lifshitz-Gilbert equation suggest that this rotation is driven solely by thermal fluctuations in the presence of a temperature gradient, whereas in thermal equilibrium it is forbidden by the Bohr-van Leeuwen theorem. We show that the rotational flow of magnons driven by the effective magnetic field of skyrmions gives rise to the skyrmion rotation, therefore suggesting that magnons can be used to control the motion of these spin textures.

Glucose hypermetabolism in the thalamus of patients with drug-induced blepharospasm.

We examined the difference in cerebral function alterations between drug-induced blepharospasm patients and essential blepharospasm (EB) patients by using positron emission tomography with (18)F-fluorodeoxyglucose. Cerebral glucose metabolism was examined in 21 patients with drug-induced blepharospasm (5 men and 16 women; mean age, 53.1 [range, 29-78] years), 21 essential EB patients (5 men and 16 women; mean age, 53.0 [range, 33-72] years) and 24 healthy subjects (6 men and 18 women; mean age, 57.9 [range, 22-78] years) with long-term history of benzodiazepines use (drug healthy subjects). Drug-induced blepharospasm patients developed symptoms while taking benzodiazepines or thienodiazepines. Sixty-three normal volunteers (15 men and 48 women; mean age, 53.6 [range, 20-70] years) were examined as controls. Differences between the patient groups and control group were examined by statistical parametric mapping. Additionally, we defined regions of interests on both sides of the thalamus, caudate nucleus, anterior putamen, posterior putamen and primary somatosensory area. The differences between groups were tested using two-sample t-tests with Bonferroni correction for multiple comparisons. Cerebral glucose hypermetabolism on both side of the thalamus was detected in drug-induced blepharospasm, EB patients and drug healthy subjects by statistical parametric mapping. In the analysis of regions of interest, glucose metabolism in both sides of the thalamus in the drug-induced blepharospasm group was significantly lower than that in the EB group. Moreover, we observed glucose hypermetabolism in the anterior and posterior putamen bilaterally in EB group but not in drug-induced blepharospasm group and drug healthy subjects. Long-term regimens of benzodiazepines or thienodiazepines may cause down-regulation of benzodiazepine receptors in the brain. We suggest that the functional brain alteration in drug-induced blepharospasm patients is similar to that in EB patients, and that alteration of the GABAergic system might be related to the pathology of both blepharospasm types.

Microwave magnetoelectric effect via skyrmion resonance modes in a helimagnetic multiferroic.

Magnetic skyrmion, a topologically stable spin-swirling object, can host emergent electromagnetism, as exemplified by the topological Hall effect and electric-current-driven skyrmion motion. To achieve efficient manipulation of nano-sized functional spin textures, it is imperative to exploit the resonant motion of skyrmions, analogously to the role of the ferromagnetic resonance in spintronics. The magnetic resonance of skyrmions has recently been detected with oscillating magnetic fields at 1-2 GHz, launching a search for new skyrmion functionality operating at microwave frequencies. Here we show a microwave magnetoelectric effect in resonant skyrmion dynamics. Through microwave transmittance spectroscopy on the skyrmion-hosting multiferroic crystal Cu2OSeO3 combined with theoretical simulations, we reveal nonreciprocal directional dichroism (NDD) at the resonant mode, that is, oppositely propagating microwaves exhibit different absorption. The microscopic mechanism of the present NDD is not associated with the conventional Faraday effect but with the skyrmion magnetoelectric resonance instead, suggesting a conceptually new microwave functionality.

Transforming growth factor-ß transiently induces vimentin expression and invasive capacity in a canine mammary gland tumor cell line.

The epithelial-mesenchymal transition (EMT) is a crucial event that occurs during cancer metastasis and can be induced by transforming growth factor-ß (TGF-ß) in various tumor cells in vitro. However, little is known about the effects of TGF-ß in canine mammary gland tumors (CMGTs). Here, we investigated the role of TGF-ß in CMGT. We observed that treatment of the CMGT cell line CHMp13a with TGF-ß1 leads to transient induction of the mesenchymal marker vimentin. Real-time measurements of cellular electrical impedance also showed that CMGT invasiveness is transiently increased by TGF-ß1 treatment, but is reversed after prolonged stimulation. This phenomenon is similar to the mesenchymal-epithelial transition (MET, the reverse phenomenon of EMT), and a process that is implicated in the establishment of secondary metastatic lesions.

Mitigation of methane production from cattle by feeding cashew nut shell liquid.

The effects of cashew nut shell liquid (CNSL) feeding on methane production and rumen fermentation were investigated by repeatedly using 3 Holstein nonlactating cows with rumen fistulas. The cows were fed a concentrate and hay diet (6:4 ratio) for 4 wk (control period) followed by the same diet with a CNSL-containing pellet for the next 3 wk (CNSL period). Two trials were conducted using CNSL pellets blended with only silica (trial 1) or with several other ingredients (trial 2). Each pellet type was fed to cows to allow CNSL intake at 4 g/100 kg of body weight per day. Methane production was measured in a respiration chamber system, and energy balance, nutrient digestibility, and rumen microbial changes were monitored. Methane production per unit of dry matter intake decreased by 38.3 and 19.3% in CNSL feeding trials 1 and 2, respectively. Energy loss as methane emission decreased from 9.7 to 6.1% (trial 1) and from 8.4 to 7.0% (trial 2) with CNSL feeding, whereas the loss to feces (trial 1) and heat production (trial 2) increased. Retained energy did not differ between the control and CNSL periods. Digestibility of dry matter and gross energy decreased with CNSL feeding in trial 1, but did not differ in trial 2. Feeding CNSL caused a decrease in acetate and total short-chain fatty acid levels and an increase in propionate proportion in both trials. Relative copy number of methyl coenzyme-M reductase subunit A gene and its expression decreased with CNSL feeding. The relative abundance of fibrolytic or formate-producing species such as Ruminococcus flavefaciens, Butyrivibrio fibrisolvens, and Treponema bryantii decreased, but species related to propionate production, including Prevotella ruminicolla, Selenomonas ruminantium, Anaerovibrio lipolytica, and Succinivibrio dextrinosolvens, increased. If used in a suitable formulation, CNSL acts as a potent methane-inhibiting and propionate-enhancing agent through the alteration of rumen microbiota without adversely affecting feed digestibility.

Origin of the large polarization in multiferroic YMnO3 thin films revealed by soft- and hard-X-ray diffraction.

We investigated the magnetic structure of an orthorhombic YMnO(3) thin film by resonant soft x-ray and hard x-ray diffraction. We observed a temperature-dependent incommensurate magnetic reflection below 45 K and a commensurate lattice-distortion reflection below 35 K. These results demonstrate that the ground state is composed of coexisting E-type and cycloidal states. Their different ordering temperatures clarify the origin of the large polarization to be caused by the E-type antiferromagnetic states in the orthorhombic YMnO(3) thin film.

Hall effect of spin-chirality origin in a triangular-lattice helimagnet Fe{1.3}Sb.

We report on a topological Hall effect possibly induced by scalar spin chirality in a quasi-two-dimensional helimagnet Fe{1+δ}Sb. In the low-temperature region where the spins on interstitial-Fe (concentration δ∼0.3) intervening the 120° spin-ordered triangular planes tend to freeze, a nontrivial component of Hall resistivity with opposite sign of the conventional anomalous Hall term is observed under magnetic field applied perpendicular to the triangular-lattice plane. The observed unconventional Hall effect is ascribed to the scalar spin chirality arising from the heptamer spin clusters around the interstitial-Fe sites, which can be induced by the spin modulation by the Dzyaloshinsky-Moriya interaction.

Effects of transplantation sites on tumour growth, pulmonary metastasis and ezrin expression of canine osteosarcoma cell lines in nude mice.

To determine the influence of the transplantation site of canine osteosarcoma (OS) cell lines on tumour growth and pulmonary metastasis, three OS cell lines were transplanted into nude mice via subcutaneous (SC), intratibial (IT) or intravenous (IV) injection. IT-xenografts exhibited greater potential for developing primary masses and pulmonary metastasis than SC-xenografts. In IT and IV xenografts, lung micrometastases along with phosphorylated ezrin-radixin-moesin (p-ERM) overexpression were found in mice xenografted with HMPOS and OOS cells after 1 week and metastasis was found with decreased p-ERM expression at later time points. The expression of ezrin and p-ERM in the primary tumours of IT-xenografted mice was higher than those in SC-xenografted mice with HMPOS and OOS cells. The results suggest that the orthotopic transplantation site plays an important role in the spontaneous metastasis of canine OS and that ezrin phosphorylation may be involved in the early metastatic mechanism of canine OS cells.

Establishment of a pair of novel cloned tumour cell lines with or without metastatic potential from canine mammary adenocarcinoma.

We produced 23 cloned cell lines from parental CHMp, which was previously established from a canine mammary adenocarcinoma patient in our laboratory. Two representative cloned cell lines, namely, CHMp-5b and -13a, were selected and characterized for cellular morphology, growth potential and expression of some tumour-related proteins. Subsequently, we transplanted the 2 tumour cell lines orthotopically into female nude mice to examine their tumorigenicity and metastatic potential. Interestingly, despite sharing the same origin, only CHMp-5b cells metastasized to the lung. Our results indicate that a comparison between these 2 cell lines at the molecular level will help us understand mechanisms of tumour progression, especially in the context of distant metastases originating from canine mammary gland tumours.