Formation of Hemihydrate Crystal form Overcomes Milling Issue Induced by Exposed Functional Groups on Cleavage Plane for a Y5 Receptor Antagonist of Neuropeptide Y.

This study aimed to investigate the crystal forms of an originally designed Y5 receptor antagonist of neuropeptide Y. Polymorphic screening was performed via solvent evaporation and slurry conversion using various solvents. The obtained crystal forms α, ß, and γ were characterized by X-ray powder diffraction analysis. Thermal analysis determined that forms α, ß, and γ were hemihydrate, metastable and stable forms, respectively; the hemihydrate and the stable forms were candidates. To arrange the particle size, forms α and γ were subjected to jet milling. However, form γ could not be milled because of powder stiction to the apparatus, whereas form α could be. To investigate this mechanism, single-crystal X-ray diffraction analysis was performed. The crystal structure of form γ was characterized by two-dimensional hydrogen bonding between neighboring molecules. This revealed that the functional groups forming hydrogen bonds were exposed on the cleavage plane of form γ. The three-dimensional hydrogen-bonding network with water stabilized the hemihydrate form, α. These results indicate that the hydrogen bondable groups exposed on the cleavage plane of form γ should result in stiction of the powder and adherence to the apparatus. It was concluded that crystal conversion is a method to overcome the milling issue.

Short-term and long-term associations with sleep onset latency in school children in Japan.

BACKGROUND: This study aims to examine the relationships between sleep onset latency and multiple sleep-related factors of seventh and tenth graders during the transition from childhood to adolescence. METHODS: Regarding sleep onset latency, we examined the short-term associations in Phase IV (2002) and long-term associations in Phase V (2005) of the Toyama Birth Cohort Study. In total, 4,673 boys and 4,694 girls in Phase IV and 2,969 boys and 3,108 girls in Phase V answered the questionnaire items regarding sleep, physical and mental health, lifestyle, socioeconomic status, and family and school factors. Considering sleep onset latency as the outcome and 13 sleep-related factors as independent variables, we calculated the odds ratio using binary logistic regression. The longitudinal study was conducted with 1,703 boys and 1,919 girls whose sleep onset latency was within 30 min in Phase IV. RESULTS: The following factors were found to be related to longer sleep onset latency in the short term: sleep duration, physical activity, game time, and self-esteem in boys and sleep duration, bedroom environment, game time, abdominal pain, long-standing illness, onset of puberty, mental health difficulties, and school avoidance feelings in girls. Regarding its long-term effects, having a single parent and self-esteem in boys and breakfast, game time, long-standing illness, obesity, onset of puberty, and school avoidance feelings in girls were associated with longer sleep onset latency. CONCLUSIONS: Education of adolescent health and sleep hygiene at home and school should include both short-term and long-term associations between sleep and a healthy lifestyle by gender.

Neighbourhood walkability and obesity among adults in rural Japan: results from a Japanese health database.

BACKGROUND: Walkable neighbourhoods promote physical activity and prevent obesity, but there is limited evidence to inform urban planning strategies for public health within the context of rural Japan. This study describes associations between neighbourhood walkability and obesity in Toyama, a regional municipality in Japan. METHODS: A cross-sectional analysis of the Toyama Prefecture National Health Insurance data (n = 3454) in 2016 using Analysis of Covariance (ANCOVA) and binary logistic regression. Walk Score® was used to estimate neighbourhood walkability. RESULTS: Residents from highly walkable neighbourhoods generally had lower mean body mass index (BMI), but significant associations between neighbourhood walkability and BMI and prevalence of obesity were only observed in women (adjusted OR: 0.46, 95% CI: 0.26-0.80). Men below 65 years old had higher obesity prevalence (adjusted OR: 1.76, 95% CI: 1.34-2.30). Daily alcohol consumption was associated with lower odds of being obese among men (adjusted OR: 0.72, 95% CI: 0.55-0.95). Hypertension, diabetes mellitus and dyslipidaemia were associated with higher obesity prevalence among residents, regardless of gender. CONCLUSIONS: Walkable environment may improve health outcomes for rural communities in Japan. Further studies are required to create equitable and inclusive living spaces for men and women to access healthier lifestyle choices.

Lifestyle, psychological stress, and incidence of adolescent constipation: results from the Toyama birth cohort study.

BACKGROUND: We aimed to clarify the predisposing factors for adolescent constipation in a longitudinal study, because while factors associated with childhood constipation have been reported, prospective studies on the incidence of constipation are lacking. METHODS: We enrolled 5540 adolescents aged 12 to 13 years from the Toyama Birth Cohort Study-a community-based prospective study examining children's health. The incidence of constipation, defined as bowel movement frequency of less than once every 2 days, was surveyed during the three-year period from baseline (grade 4) to follow-up (grade 7). Multivariate logistic regression analyses were performed to explore the association between the incidence of adolescent constipation and their lifestyle variables. RESULTS: A total of 261 adolescents (4.7%) developed constipation during the three-year period. Female sex (odds ratio [OR] = 2.62,) overweight (OR = 0.60), and infrequent intake of fruits (OR = 1.50) at baseline were associated with the incidence of constipation. Furthermore, factors related to lifestyle changes and psychological status such as skipping breakfast (OR = 1.73), becoming physically inactive (OR = 1.55), and being persistently irritated (OR = 1.80) were significantly associated with the incidence of constipation. CONCLUSION: Our prospective study demonstrated that female sex, insufficient fruit intake, and deteriorating lifestyles such as skipping breakfast and becoming inactive during the 3-year period were associated with the incidence of adolescent constipation. Beyond anecdotal, maintaining a healthy lifestyle is recommended to reduce the incidence of adolescent constipation.

The Relationship Between Quality of Life and Pubertal Timing in Adolescence: The Toyama Birth Cohort Study, Japan.

PURPOSE: Although pubertal timing is gradually becoming earlier in Japan, support as for physical and mental health among children experiencing earlier puberty than their peers is inadequate. To better understand health and life satisfaction in seventh grade students (age 12-13 years), examination of relationships between health outcomes and pubertal timing, socioeconomic status, and lifestyle factors is necessary. METHODS: Participants of the Toyama Birth Cohort Study (4,752 males and 4,740 females) answered questions regarding school year of onset of voice break for boys and menarche for girls, sleep quality, mental health difficulties, overall health, quality of life (QOL), and lifestyle. Relationship between health outcomes and pubertal timing was examined using binary logistic regression analysis. RESULTS: Earlier pubertal timing was associated with four health-related outcomes. For poor sleep quality, the adjusted odds ratio (OR) of fourth grade males and crude OR of fifth grade females were statistically significant. Regarding mental health difficulties, the crude OR of fifth grade males and adjusted OR of fourth, fifth, and sixth grade females were statistically significant. Associations between poor overall health and fourth grade males and fourth or fifth grade females were observed. For poor QOL, the adjusted OR of fourth grade males and females was statistically significant. CONCLUSIONS: Relationships between earlier pubertal timing and poor sleep quality, mental health difficulties, poor physical health, and poor QOL were observed. To improve children's quality of life, support from teachers and school doctors and nurses is needed-especially for children with earlier pubertal timing.

Correction to Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).

[This corrects the article DOI: 10.1021/acsomega.8b01481.].

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).

We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure-activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.

Lifestyle and overall health in high school children: Results from the Toyama birth cohort study, Japan.

BACKGROUND: The aim of this study was to investigate the relationship between lifestyle and overall health in high school children. METHODS: Subjects were from the Toyama Birth Cohort Study, a prospective, longitudinal study of children born between 1989 and 1990, and who lived in Toyama Prefecture, Japan, at the time of the survey. This investigation used data from phase 5 of the Birth Cohort Study, which was conducted in 2005, when the children were in high school. Participants included 4,966 children (2,449 boys and 2,517 girls) aged 15-16 years old. A questionnaire was designed to measure lifestyle factors such as eating habits, physical activity, sedentary behavior, and sleeping pattern. A question from a validated Japanese version of the Dartmouth Primary Care Cooperative Information Project was used to evaluate overall health in children. Logistic regression analysis was used to determine if lifestyle factors are associated with overall health in high school children. RESULTS: Boys who skipped breakfast and had short night-time sleep duration (≤6 h per night) were more likely to have poor health status. Girls who skipped breakfast, and had night-time eating patterns, personal computer use >4 h per day, and short night-time sleep duration (≤6 h/night) were more likely to have poor health status. CONCLUSIONS: Undesirable lifestyle was associated with poor health status in high school boys and girls. Further understanding of these relationships is needed to facilitate the development of interventions that will help children with poor health status.

Triazole- and Tetrazole-Bridged Nucleic Acids: Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro and in Vivo Antisense Potency.

Antisense oligonucleotides are attractive therapeutic agents for several types of disease. One of the most promising modifications of antisense oligonucleotides is the introduction of bridged nucleic acids. As we report here, we designed novel bridged nucleic acids, triazole-bridged nucleic acid (TrNA), and tetrazole-bridged nucleic acid (TeNA), whose sugar conformations are restricted to N-type by heteroaromatic ring-bridged structures. We then successfully synthesized TrNA and TeNA and introduced these monomers into oligonucleotides. In UV-melting experiments, TrNA-modified oligonucleotides exhibited increased binding affinity toward complementary RNA and decreased binding affinity toward complementary DNA, although TeNA-modified oligonucleotides were decomposed under the annealing conditions. Enzymatic degradation experiments demonstrated that introduction of TrNA at the 3'-terminus rendered oligonucleotides resistant to nuclease digestion. Furthermore, we tested the silencing potencies of TrNA-modified antisense oligonucleotides using in vitro and in vivo assays. These experiments revealed that TrNA-modified antisense oligonucleotides induced potent downregulation of gene expression in liver. In addition, TrNA-modified antisense oligonucleotides showed a tendency for increased liver biodistribution. Taken together, our findings indicate that TrNA is a good candidate for practical application in antisense methodology.

Effect of an N-substituent in sulfonamide-bridged nucleic acid (SuNA) on hybridization ability and duplex structure.

A sulfonamide-bridged nucleic acid without an N-substituent (SuNA[NH]) was successfully synthesized. A comparison of the SuNA[NMe]- and SuNA[NH]-modified oligonucleotides revealed that the duplex-forming abilities of the SuNA[NMe]-modified oligonucleotides with complementary DNA and RNA were higher than those of the SuNA[NH]-modified oligonucleotides. The crystal structures of DNA duplexes containing a SuNA[NR] revealed that the helical structures of the two duplexes and hydration patterns around the bridge moiety were different. These results provide insights into hydration patterns and rationale for the high RNA affinity of SuNA-modified oligonucleotides.

Association among number, order and type of siblings and adolescent mental health at age 12.

BACKGROUND: Although the sibling relationship is a unique one, the effects of the number and type of siblings on mental health among adolescents have not been reported. METHODS: Japanese children (total, 9276; boys, 4654; girls, 4622), all 12 years old, and from the Japanese Toyama Birth Cohort Study, were followed up until 2002. Subject self-reported mental health was obtained from the Japanese version of the Dartmouth Primary Care Co-operative Project (COOP) charts. The associations between number and type of siblings and self-reported mental health were examined. RESULTS: There was a significant difference in mental health between different sibling pairs, with brother pairs and brother/sister pairs having a positive effect on adolescent mental health, compared with those in sister pairs. Girls with brothers had better self-reported mental health than those without. The adjusted OR of good mental health was 1.44 (95%CI:1.00-2.08) for those with an older brother and 1.67 (95%CI: 1.17-2.38) for those with a younger brother compared with those without. Boys with a younger sister had a higher OR of good self-reported health than those without (OR, 1.62; 95%CI: 1.08-2.43). CONCLUSIONS: Children with siblings had better mental health status than those without, which has practical implications for Asian countries and worldwide considering the declining fertility.

Sex differences in factors contributing to family-to-work and work-to-family conflict in Japanese civil servants.

OBJECTIVES: As the number of dual-earner couples in Japan has increased, work-life balance has become important. This study aimed to examine the factors that contribute to work-family conflict. METHODS: The participants included 3,594 (2,332 men and 1,262 women) civil servants aged 20-59 working for local government on the west coast of Japan. Logistic regression analysis was used to evaluate whether work, family, or lifestyle characteristics were associated with work-family conflict. RESULTS: For men, family-to-work conflict was associated with being elderly, having low-grade employment, working long hours, raising children, and sleeping shorter hours. For women, being married and raising children were strong determinants of family-to-work conflict, and being middle-aged, working long hours, and sleeping shorter hours were also associated with this type of conflict. Regarding work-to-family conflict, working long hours was the strongest determinant of conflict in both sexes. In men, being elderly, living with family, eating dinner late, and sleeping shorter hours were also associated with work-to-family conflict. In women, having high-grade employment, being married, raising children, and eating dinner late were associated with work-to-family conflict. CONCLUSIONS: This study showed that working long hours was the primary determinant of work-to-family conflict in both sexes and that being married and raising children were strong factors of family-to-work conflict in women only. Sex differences may reflect divergence of the social and domestic roles of men and women in Japanese society. To improve the work-life balance, general and sex-specific health policies may be required.

Sulfonamide-bridged nucleic acid: synthesis, high RNA selective hybridization, and high nuclease resistance.

2'-N,4'-C-(N-methylamino)sulfonylmethylene-bridged thymidine (SuNA), which has a six-membered linkage including a sulfonamide moiety, was synthesized and introduced into oligonucleotides. The oligonucleotides containing SuNA exhibited excellent nuclease resistance, a high affinity toward single-stranded RNA, and a low affinity toward single-stranded DNA compared to the natural oligonucleotide.

Family history of hypertension and the risk of overweight in Japanese children: results from the Toyama Birth Cohort Study.

BACKGROUND: Family history can be a useful screening tool in the assessment and management of the risk for noncommunicable disease. However, no data have yet been reported on family history of hypertension and its effect on children's overweight. METHODS: A total of 7249 Japanese children enrolled in the Toyama Birth Cohort Study were followed until 2002 (mean age: 12.3 years). Family history of hypertension was ascertained by asking children's parents whether children's biological parents or grandparents had doctor-diagnosed hypertension. Child overweight was defined according to international criteria for age- and sex-specific body mass index. RESULTS: The prevalence of child overweight at age 12 was 21.7% for males and 15.9% for females. After adjusting for family structure, parental employment status, and lifestyle factors, we found that a maternal family history of hypertension was positively associated with the risk of child overweight at age 12 (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.04-1.39). The adjusted OR increased from 1.16 (95% CI 0.99-1.35) to 1.42 (95% CI 1.04-1.92) to 4.75 (95% CI 1.35-16.69) as the number of family members with hypertension increased from 1 to 2 to 3, respectively. There was no significant difference in the prevalence of overweight between children with a paternal family history of hypertension and those without. CONCLUSIONS: A maternal family history of hypertension was positively associated with the risk of overweight in children at age 12.

Physicochemical characterization and structural evaluation of a specific 2:1 cocrystal of naproxen-nicotinamide.

Physicochemical characterization and structural evaluation of a 2:1 naproxen-nicotinamide cocrystal were performed. The 2:1 cocrystal showed rapid naproxen dissolution and less water vapor adsorption, indicating better pharmaceutical properties of naproxen. The unique 2:1 cocrystal formation was evaluated by solid-state nuclear magnetic resonance (NMR). The assignments of all H and (13) C peaks for naproxen and the cocrystal were performed using dipolar-insensitive nuclei enhanced by polarization transfer and (1) H-(13) C cross-polarization (CP)-heteronuclear correlation (HETCOR) NMR measurements. The (13) C chemical shift revealed that two naproxen molecules and one nicotinamide molecule existed in the asymmetric unit of the cocrystal. The (1) H chemical shifts indicated that the carboxylic group of the naproxen in the cocrystal was nonionized, and the CH-π interaction between naproxens was very strong. From the (1) H-(13) C CP-HETCOR NMR spectrum with contact time of 5 ms, two different synthons, carboxylic acid-amide and carboxylic acid-pyridine ring, were found between naproxen and nicotinamide. Single-crystal X-ray analysis, which supported the solid-state NMR results, clarified the geometry and intermolecular interactions in more detail. The structure is unique among pharmaceutical cocrystals because each carboxyl group of the two naproxens formed different intermolecular synthons.

Inpatient satisfaction and job satisfaction/stress of medical workers in a hospital with the 7:1 nursing care system (in which 1 nurse cares for 7 patients at a time).

OBJECTIVES: Inpatient satisfaction, job satisfaction/stress of medical workers, and hospital profitability under the 7:1 nursing care system (in which 1 nurse cares for 7 patients at a time) were compared with those under the 10:1 system at a hospital with the diagnosis procedure combination (DPC) payment system. METHODS: A total of 202 inpatients discharged from the Departments of Cardiology and Metabolism completed an inpatient satisfaction questionnaire. A total of 108 medical workers were recruited to survey their job satisfaction/stress and to estimate the effects of the DPC. The profits for 10 cardiac and metabolic diseases in 2008 were compared with those in 2007. RESULTS: Mean inpatient satisfaction scores were around 4 ("somewhat satisfied") under both the 10:1 and 7:1 systems, and increased significantly to 4.14-4.38 under the 7:1 system. Excluding workload of physicians, the other stresses of physicians/nurses remained unaltered, as did their low job satisfaction. They estimated their understanding of the DPC as insufficient but felt that introducing the DPC neither shortened length of stay nor improved "the quality of medical/nursing care," regardless of the system. Total percentage profit in 2008 was almost the same as that in 2007, whereas diseases with deficits increased from 3 to 4. [corrected] CONCLUSIONS: The 7:1 system was somewhat beneficial for inpatients but not always for medical worker quality of life (QOL) or for hospital income, which are important to maintain high quality of medical/nursing care. It is important to further explore factors increasing QOL of medical workers and hospital income.