Hormonal and Neurological Aspects of Dog Walking for Dog Owners and Pet Dogs.

The hormone oxytocin is involved in various aspects of the relationship between humans and animals. Dog walking is a common activity for dog owners and their dogs. The walk, of course, should be good for the health of the dog as well as its owner. In Experiment I, we assessed whether salivary oxytocin and cortisol in dog owners changed because of walking their dogs. Ten owners walked with their dogs and walked alone. Similar to other previous research, walking with a dog did not significantly change oxytocin and cortisol. Therefore, in Experiment II, we investigated the effect of dog walking on brain noradrenergic and GABAergic neural activity, as indicated by salivary MHPG and GABA, in 14 dog owners. Walking with a dog reduced salivary MHPG compared to walking alone, and MHPG was correlated negatively with GABA. Thus, dog walking activated GABAergic nerves in the brain and suppressed noradrenergic nerves, effectively relieving stress.

The Urinary Hormonal State of Cats Associated With Social Interaction With Humans.

Research to assess the relationship between cats and humans is in a nascent stage. Some studies have assessed the stress status in cats using physiological indicators, such as the cortisol hormone, but have not focused on the social interaction with humans. Moreover, the role of oxytocin secretion in the relationship between cats and humans remains unclear. In this study, we determined the possibility of quantifying the urinary concentration of oxytocin in cats and assessed the effects of social contact with humans on the levels of urinary oxytocin and cortisol metabolite. Four cats were subjected to two conditions, namely, social (control), and non-social (no social contact with humans) conditions. The levels of cortisol and oxytocin metabolite in urine samples from the cats in both conditions were determined using enzyme-linked immunosorbent assays. The urinary concentrations of cortisol and oxytocin under the non-social condition were significantly higher than those under the social condition. In addition, the concentration of oxytocin significantly correlated with that of cortisol in cats under the non-social condition. In this study, it was possible to quantify the concentration of oxytocin in the urine of cats, and the obtained results suggest that cats recognize the social interaction with humans as important. This information might contribute to the establishment of an assessment method for the welfare of cats and might help in clarifying the relationship between cats and humans.

Effects of the characteristic temperament of cats on the emotions and hemodynamic responses of humans.

Cats positive effects on their owners' physiological and psychological health, including improved mood and activation of the human prefrontal cortex and inferior frontal gyrus in the brain. However, the association between the health benefits provided by cat ownership and the characteristic behaviors and reactions of cats is unclear. We recruited 29 participants to measure human prefrontal cortex activity, using functional near-infrared spectroscopy, during interactions with a cat. After the experiments, participants subjectively responded to a questionnaire regarding success rates for interactions with the cat, and completed the Self-assessment Manikin-a scale used to measure emotion. Interactions comprised eight types in four categories (touch, play, train, and feed). This study showed that interactions with a cat significantly activated the prefrontal cortex, regardless of interaction type. During training, the integral values of oxygenated hemoglobin in the left inferior frontal gyrus were the highest in all the interaction categories; however, success rates were lower than in the touch and feed interactions. Regarding the Self-assessment Manikin scores, all interaction categories showed a positive correlation between success rate and valence score, especially in the train and play interactions than in the touch and feed interactions. These results indicate that interactions with a cat activate the prefrontal cortex in humans, including the inferior frontal gyrus region. Moreover, cats' autonomous behaviors and reactions positively influenced the participants. The characteristic temperament of cats may be a key factor influencing the health benefits of owning cats.

A possible mechanism of horseback riding on dynamic trunk alignment.

The study aimed to clarify the regularity of the motions of horse's back, rider's pelvis and spine associated with improvement of rider's dynamic trunk alignment. The study used a crossover design, with exercise using the horseback riding simulator (simulator hereafter) as the control condition. The experiments were conducted at Tokyo University of Agriculture Bio-therapy Center. The sample consisted of 20 healthy volunteers age 20-23 years. Participants performed 15-min sessions of horseback riding with a Hokkaido Pony and exercise using the simulator in experiments separated by ≥2 weeks. Surface electromyography (EMG) after horseback riding revealed decreased activity in the erector spinae. Exploratory data analysis of acceleration and angular velocity inferred associations between acceleration (Rider's neck/longitudinal axis [Y hereafter]) and angular velocity (Horse saddle/Y) as well as angular velocity (Rider's pelvis/Y) and angular velocity (Horse saddle/Y). Acceleration (Rider's neck/Y) tended to be associated with angular velocity (Rider's pelvis/Y). Surface EMG following exercise revealed decreased activity in the rectus abdominis and erector spinae after the simulator exercise. Horseback riding improved the rider's dynamic trunk alignment with a clear underlying mechanism, which was not observed with the simulator.

Statistical Evaluations of Variations in Dairy Cows' Milk Yields as a Precursor of Earthquakes.

Previous studies have provided quantitative data regarding unusual animal behavior prior to earthquakes; however, few studies include long-term, observational data. Our previous study revealed that the milk yields of dairy cows decreased prior to an extremely large earthquake. To clarify whether the milk yields decrease prior to earthquakes, we examined the relationship between earthquakes of various magnitudes and daily milk yields. The observation period was one year. In the results, cross-correlation analyses revealed a significant negative correlation between earthquake occurrence and milk yields approximately three weeks beforehand. Approximately a week and a half beforehand, a positive correlation was revealed, and the correlation gradually receded to zero as the day of the earthquake approached. Future studies that use data from a longer observation period are needed because this study only considered ten earthquakes and therefore does not have strong statistical power. Additionally, we compared the milk yields with the subionospheric very low frequency/low frequency (VLF/LF) propagation data indicating ionospheric perturbations. The results showed that anomalies of VLF/LF propagation data emerged prior to all of the earthquakes following decreases in milk yields; the milk yields decreased earlier than propagation anomalies. We mention how ultralow frequency magnetic fields are a stimulus that could reduce milk yields. This study suggests that dairy cow milk yields decrease prior to earthquakes, and that they might respond to stimuli emerging earlier than ionospheric perturbations.

Horseback Riding Improves the Ability to Cause the Appropriate Action (Go Reaction) and the Appropriate Self-control (No-Go Reaction) in Children.

BACKGROUND: There are many obvious health benefits to riding, including developing a strong core and legs, but there are also many less obvious benefits, such as increased confidence and introspection. Few studies have addressed the effects of horseback riding on children and the mechanisms underlying how riding affects humans. We examined the effects of horseback riding on the ability to distinguish Go/No-go tasks and solve arithmetic problems in children. METHODS: The subjects were 34 boys and 72 girls, aged 10-12 years old, which were divided into three groups (horse riding, walking, and resting). They were healthy typical children, who performed the Go/No-go tasks and solved the arithmetic problems. The heart rate and heart rate variability of the children, and the three-dimensional acceleration of the children while walking horses, were examined. RESULTS: Riding on a half-breed horse or a pony improved the ability to perform Go/No-go tasks and solve arithmetic problems, possibly through sympathetic activity. Some horses, like the Kiso, might provide a healing effect to children through parasympathetic activity. Statistically significant differences in the three-dimensional acceleration and the autonomic activities were observed among the three horses. The acceleration in the Kiso horse group during walking in hand was significantly different from those involving the other two horses, indicating that the vibrations produced by these horses might modify the autonomic activities. CONCLUSION: The most important beneficial factor of horseback riding for children and for human health appears to be associated with the horse's vibrations, which may differ among horses. Riding some horses may improve the ability of children to respond with an appropriate action depending on the situation (Go reaction) or use self-control appropriately (No-go reaction), possibly through the activation of the sympathetic nervous system.

Increased Feeding Speed Is Associated with Higher Subsequent Sympathetic Activity in Dogs.

Although the domestication process has altered the feeding behavior of dogs, some breeds still demonstrate a remarkable ability to gorge, and will eat exceptionally large quantities of food whenever it is available. Lesions in the ventromedial hypothalamus increase appetite and lead to obesity, suggesting that the autonomic nervous system plays an important role in feeding. Focusing on the autonomic activities closely involved in food intake, we investigated sympathetic activities before and after feeding in dogs. The subjects were 56 healthy dogs of 21 different breeds (29 males and 27 females). Based on feeding habits, the 56 dogs were divided into three groups: Fast (n = 19), Slow (n = 24) and Leftover (n = 13). The feeding speed and the amount of food per mouthful of the Fast dogs were significantly greater than those of the Slow and the Leftover dogs. The plasma norepinephrine level in dogs of the Fast group was significantly increased after feeding, while those in the Slow and Leftover groups were significantly decreased after feeding, compared with the pre-feeding concentrations. The low frequency/high frequency ratio of heart rate variability is a good indicator of sympathetic activity and was also significantly higher in the Fast group than in the other groups. Delayed feeding using automatic feeding equipment decreased the plasma norepinephrine concentration and low frequency/high frequency ratio observed after feeding in dogs of the Fast group. In conclusion, dogs eating rapidly with less chewing, which indicates increased sympathetic activity during feeding, may benefit from delayed feeding. The slow eating may activate the parasympathetic nervous system after feeding, which could enhance the activity of the digestive system.

Social evolution. Oxytocin-gaze positive loop and the coevolution of human-dog bonds.

Human-like modes of communication, including mutual gaze, in dogs may have been acquired during domestication with humans. We show that gazing behavior from dogs, but not wolves, increased urinary oxytocin concentrations in owners, which consequently facilitated owners' affiliation and increased oxytocin concentration in dogs. Further, nasally administered oxytocin increased gazing behavior in dogs, which in turn increased urinary oxytocin concentrations in owners. These findings support the existence of an interspecies oxytocin-mediated positive loop facilitated and modulated by gazing, which may have supported the coevolution of human-dog bonding by engaging common modes of communicating social attachment.

Experimental Verification of the Effects on Normal Domestic Cats by Feeding Prescription Diet for Decreasing Stress.

The objective of this study was to evaluate the effects of diet on the feline stress response by measuring plasma and urinary cortisol. A study diet was developed with a unique combination of nutrients that supports the management of stressful situations. The specific formulation of the diet included alpha-casozepine, which is believed to have an anxiolytic effect, and tryptophan supplementation. Tryptophan is the precursor for the synthesis of the neurotransmitter serotonin. Twenty-one indoor cats were fed with the study diet (n = 10) or a control diet (n = 11) for 8 weeks, after which physiological responses were evaluated. The study diet significantly increased the ratio of plasma tryptophan to large neutral amino acids and decreased urinary cortisol concentrations after being consumed daily for 8 weeks, but there was no effect on plasma cortisol levels following a stressful event (veterinary examination and blood draw). Further studies, such as behavioral analyses, are needed to clarify the effects of the study diet.

Psychological Evaluation of Animal-assisted Intervention (AAI) Programs Involving Visiting Dogs and Cats for Alcohol Dependents: A Pilot Study.

The purpose of this study was to develop an evaluation method for animal-assisted intervention (AAI) programs involving Mood Check List-Short form.2 (MCL-S.2) and the State-Trait Anxiety Inventory (STAI) for psychiatric daycare of Japanese alcohol. dependents. A total of 36 alcohol dependents completed the study and questionnaires assessing their state. A single session of AAI reduced both subjective and physiological measures of state anxiety (A-State); and this program induced a significant reduction in the anxiety after an AAI program session with the dogs and cats involved in the intervention (p = 0.001). The Wilcoxon t-test showed that there were also significant differences in the "anxiety", "pleasantness", and "relaxation". scores for MCL-S.2 among the alcohol dependents, before and after AAI; a significantly decreased "anxiety" score (p = 0.006), and increased "pleasantness" (p = 0.002) and "relaxation" (p=0.012) scores for MCL-S.2 after AAI. The results of this study indicated that alcohol dependents who experienced a group AAI session-program exhibited significant improvements in their feeling; decreased anxiety, and increased pleasantness and relaxation.

Dogs' Body Language Relevant to Learning Achievement.

The facial expressions and body postures of dogs can give helpful information about their moods and emotional states. People can more effectively obedience train their dogs if we can identify the mannerisms associated with learning in dogs. The aim of this study was to clarify the dog's body language during operant conditioning to predict achievement in the test that followed by measuring the duration of behaviors. Forty-six untrained dogs (17 males and 26 females) of various breeds were used. Each session consisted of 5 minutes of training with a treat reward followed by 3 minutes of rest and finally an operant conditioning test that consisted of 20 "hand motion" cues. The operant tests were conducted a total of nine times over three consecutive days, and the success numbers were counted. The duration of the dog's behavior, focusing on the dog's eyes, mouth, ears, tail and tail-wagging, was recorded during the operant conditioning sessions before the test. Particular behaviors, including wide-eyes, closed mouth, erect ears, and forward and high tail carriage, without wagging or with short and quick wagging, related to high achievement results. It is concluded that dogs' body language during operant conditioning was related to their success rate.

Unusual Animal Behavior Preceding the 2011 Earthquake off the Pacific Coast of Tohoku, Japan: A Way to Predict the Approach of Large Earthquakes.

Unusual animal behaviors (UABs) have been observed before large earthquakes (EQs), however, their mechanisms are unclear. While information on UABs has been gathered after many EQs, few studies have focused on the ratio of emerged UABs or specific behaviors prior to EQs. On 11 March 2011, an EQ (Mw 9.0) occurred in Japan, which took about twenty thousand lives together with missing and killed persons. We surveyed UABs of pets preceding this EQ using a questionnaire. Additionally, we explored whether dairy cow milk yields varied before this EQ in particular locations. In the results, 236 of 1,259 dog owners and 115 of 703 cat owners observed UABs in their pets, with restless behavior being the most prominent change in both species. Most UABs occurred within one day of the EQ. The UABs showed a precursory relationship with epicentral distance. Interestingly, cow milk yields in a milking facility within 340 km of the epicenter decreased significantly about one week before the EQ. However, cows in facilities farther away showed no significant decreases. Since both the pets' behavior and the dairy cows' milk yields were affected prior to the EQ, with careful observation they could contribute to EQ predictions.

Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists.

To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.

Discovery of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol: a novel, potent and selective type 5 17ß-hydroxysteroid dehydrogenase inhibitor.

Type 5 17ß-hydroxysteroid dehydrogenase (17ß-HSD5), also known as aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily of enzymes and is expressed in the human prostate. One of the main functions of 17ß-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5α-dihydrotestosterone (DHT) in patients following chemical or surgical castration has been reported to remain as high as 39% of that of healthy men, with 17ß-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17ß-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC). To investigate this, we conducted high-throughput screening (HTS) and identified compound 2, which displayed a structure distinct from known 17ß-HSD5 inhibitors. To optimize the inhibitory activity of compound 2, we first introduced a primary alcohol group. We then converted the primary alcohol group to a tertiary alcohol, which further enhanced the inhibitory activity, improved metabolic stability, and led to the identification of compound 17. Oral administration of compound 17 to castrated nude mice bearing the CWR22R xenograft resulted in the suppression of androstenedione (AD)-induced intratumoral testosterone production. Compound 17 also demonstrated good isoform selectivity, minimal inhibitory activity against either CYP or hERG, and enhanced pharmacokinetic and physicochemical properties.

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: discovery of YM543.

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.

Importance of puppy training for future behavior of the dog.

In this study, we attempted to clarify whether puppy socialization and command training class, which was limited to puppies approximately 4 months of age, prevented behavior problems in dogs. We evaluated the behaviors of 142 dogs with 4 types of training experience by using a behavior test and the Canine Behavior Assessment and Research Questionnaire (C-BARQ). Dogs in the puppy class (PC) group (n=44) attended the class for 1 hr each week for 6 weeks, dogs in the puppy party (PP) group (n=39) attended a 1-hr "puppy party," dogs in the adult class (AC) group (n=27) undertook basic obedience lessons for adolescent/adult dogs for 1 hr each week for 6 weeks, and dogs in the no class (NC) group (n=32) underwent no formal training. The behavior test evaluated each dog's response to commands, owner's recall, separation, a novel stimulus and strangers. The C-BARQ evaluated 15 canine behavioral factors. The behavior test results indicated that the PC and AC groups showed significantly higher response to commands than the PP or NC group. Thus, participation in puppy and adult classes improved the obedience behavior of dogs, regardless of age. Positive response to strangers in the PC group was significantly higher than that in the AC and NC groups and tended to be higher than that in the PP group. Therefore, PC may help prevent canine behavioral problems such as disobedience or fear of strangers.

Pyrrolidinyl phenylurea derivatives as novel CCR3 antagonists.

Optimization starting with our lead compound 1 (IC(50)=4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC(50)=1.7 nM), a potent and orally active CCR3 antagonist.

Synthesis and structure-activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists.

A series of fused-pyrimidine derivatives have been discovered as potent and orally active GPR119 agonists. A combination of the fused-pyrimidine structure and 4-chloro-2,5-difluorophenyl group provided the 5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide derivative 14a as a highly potent GPR119 agonist. Further optimization of the amino group at the 4-position in the pyrimidine ring led to the identification of 2-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetamide (16b) as an advanced analog. Compound 16b was found to have extremely potent agonistic activity and improved glucose tolerance at 0.1 mg/kg po in mice. We consider compound 16b and its analogs to have clear utility in exploring the practicality of GPR119 agonists as potential therapeutic agents for the treatment of type 2 diabetes mellitus.

Orally available pyridinylpyrimidine derivatives as novel RANKL-induced osteoclastogenesis inhibitors.

An HTS campaign led to the identification of 4-pyrroldino-2-(pyridin-2-yl)pyrimidine compound 1 as an RANKL-induced osteoclastogenesis inhibitor. The compound 1 showed high clearance values in microsomes, however. Modification of the pyrrolidino group to a benzylamino group improved human microsomal stability with a slight loss of in vitro activity. Substitution at the ortho position of the benzyl group ameliorated in vitro activity, and further fluorination of the benzyl group improved microsomal stability in rodents. Representative members of this series, compounds 20 and 23, exhibited efficacy in RANKL-induced osteopenic mice when administered orally at 0.3 mg/kg.