Evaluating the cross-cultural competence instrument for healthcare professionals (CCCHP) among nurses in Okinawa, Japan.

BACKGROUND: To provide better quality healthcare services to patients with different linguistic and cultural backgrounds, the cross-cultural competence of medical professionals is important. However, assessing and improving the cross-cultural competence of healthcare professionals is difficult in Japan, as there is no standardized scale to measure the competence. This study's purpose was to translate the Cross-Cultural Competence instrument for Healthcare Professionals (CCCHP), which was developed and used in Europe, and to examine its reliability and validity among Japanese nurses. METHODS: During June and July 2021, nursing staff were invited to take web- and paper-based surveys in Okinawa Japan. The CCCHP (five-factor model with 27 items across motivation, attitude, skills, emotion, and knowledge) was translated using a combination translation method, and a five-point Likert scale was used for responses. Exploratory and confirmatory factor analyses and known-group method were used to examine structural validity, while Cronbach's alpha coefficient was used to test reliability. RESULTS: A total of 294 responses were analyzed; 77.2% had more than five years of experience. Since the fit index indicated that the five-factor model was not a good fit, it was modified to a four-factor model (J-CCCHP24) by moving three variables, removing the knowledge factor, and using the error covariance of the variables. The fit index after the modification was improved to comparative fit index (CFI) = 0.92, Tucker-Lewis index (TLI) = 0.91, root mean square error of approximation (RMSEA) = 0.05, and standardized root mean square residual (SRMR) = 0.06, and Cronbach's alpha was 0.85. The mean scores of J-CCCHP24 were significantly higher in the group with a history of overseas travel, higher foreign language skill, training in intercultural care, experience of foreign patient care, and intercultural interactions outside the workplace than in the group without these characteristics. CONCLUSION: This study confirmed the validity and reliability of the modified Japanese version of the CCCHP (four-factor model with 24 items). The results suggest that the exposure to different cultures on a personal level may help improve nurses' cross-cultural competence. Further refinement of this scale for practical use would encourage the implementation of necessary countermeasures to improve the cross-cultural competence of Japanese healthcare professionals.

Efficacy of KPR-5714, a selective transient receptor potential melastatin 8 antagonist, on chronic psychological stress-induced bladder overactivity in male rats.

AIMS: Chronic psychological stress aggravates lower urinary tract symptoms. Among others, water avoidance stress is a chronic psychological stressor that plays a causal role in the exacerbation and development of bladder dysfunction in rats. In this report, the effects of KPR-5714, which is a selective transient receptor potential melastatin 8 (TRPM8) antagonist, on bladder overactivity induced by water avoidance stress were examined. METHODS: Male rats were subjected to water avoidance stress for 2 h per day for 10 consecutive days. The effects of water avoidance stress on voiding behavior using metabolic cages and histological bladder changes were investigated in rats. The involvement of bladder C-fiber afferent on voiding frequency in rats exposed to water avoidance stress was assessed using capsaicin. The effects of KPR-5714 on storage dysfunction in rats subjected to water avoidance stress were examined. RESULTS: In voiding behavior measurements, water avoidance stress-induced storage dysfunction, causing a decrease in the mean voided volume and increasing voiding frequency. A comparison of bladders from normal rats and rats exposed to water avoidance stress showed no histological differences. Water avoidance stress-induced bladder overactivity was completely inhibited by pretreatment with capsaicin. KPR-5714 showed a tendency to increase the mean voided volume and significantly decreased the voiding frequency without affecting the total voided volume in these rats. CONCLUSION: The results suggest that KPR-5714 is a promising option for treating chronic psychological stress-induced bladder overactivity.

Immature Platelet Fraction and Its Kinetics in Neonates.

Thrombocytopenia is a common abnormality encountered in the neonatal period, and immature platelet fraction (IPF) may be an informative indicator of thrombopoiesis; however, data on IPF in neonates are scarce. To define reference intervals (RIs) and factors affecting IPF in neonates, we measured the IPF of 533 consecutive neonates. With a multiple regression analysis of 330 newborns with normal platelet counts at birth, premature delivery, neonatal asphyxia, intrauterine infection, chromosomal abnormalities, and respiratory disorders were identified as independent factors for IPF%. The RIs of IPF% and absolute IPF value in neonates were determined to be 1.3% to 5.7% and 3.2 to 14.5×10 9 /L, respectively. On day 14 after birth, IPF% increased to twice the value at birth and thereafter returned to the previous value on day 28. Reticulocyte counts, in contrast, were the lowest at day 14. IPF% was increased in 16 thrombocytopenic patients with various clinical conditions, especially those with immune-mediated thrombocytopenia. IPF in neonates may be evaluated essentially based on the same RIs as in adults, although some precautions must be taken when evaluating IPF in neonates in the first 2 weeks of life. IPF may be useful for evaluating thrombopoiesis and thrombocytopenia in neonates.

Activation of the TLR4-JNK but not the TLR4-ERK pathway induced by indole-3-acetic acid exerts anti-proliferative effects on Caco-2 cells.

We previously found that indole-3-acetic acid (IAA) produced from tryptophan by gut microbiota decreases the expression of tumor necrosis factor α (TNFα), which is implicated in the pathogenesis of colorectal cancer (CRC). The present study aimed to determine IAA involvement in the proliferation of CRC-derived Caco-2 cells. Cell proliferation was suppressed by IAA, whereas IAA-induced aryl hydrocarbon receptor activation had no impact. IAA activated extracellular signal-related (ERK) and c-Jun N-terminal (JNK) kinases, but not p38. Toll-like receptor 4 (TLR4) may be required to activate ERK and JNK, but only the TLR4-JNK pathway might elicit the anti-proliferative effects of IAA. Thus, IAA may be a ligand for TLR4 that contributes to inhibiting CRC cell proliferation by activating TLR4-mediated JNK. Because IAA did not induce cytotoxicity, inhibiting cell cycle progression might affect the anti-proliferative capacity of IAA. Therefore, colonic IAA accumulation might help to prevent CRC development and progression.

The oral disposition index calculated from a meal tolerance test is a crucial indicator for evaluating differential normalization of postprandial glucose and triglyceride excursions in morbidly obese patients after laparoscopic sleeve gastrectomy.

To determine the normalization of postprandial blood glucose (PG) and triglyceride (TG) excursions in 30 morbidly obese patients with or without diabetes mellitus (DM) 1-year after they underwent a laparoscopic sleeve gastrectomy (LSG) vs. their pre-surgery data, we administered the 75-g oral glucose tolerance test (OGTT) and a meal tolerance test (MTT) using a 75-g glucose-equivalent carbohydrate- and fat-containing meal. The results were as follows; (i) Postoperative body-weight reduction was associated with DM remission and reduced multiple cardiometabolic risks. (ii) OGTT data showing postprandial hyper-insulinemic hypoglycemia in many post-surgery patients were associated with overdiagnosis of improved glucose tolerance. However, postoperative MTT data without hypoglycemia showed no improvement in the glucose tolerance vs. pre-surgery data. (iii) The disposition index (DI) i.e., [Matsuda index] × (Glucose-induced insulin secretion) was progressively worsened from normal glucose tolerance to DM patients after LSG. These post-surgery DI values measured by the MTT were correlated with 2h-plasma glucose levels and were not normalized in DM patients. (iv) The baseline, 2h-TG, and an increase in 2h-TG values above baseline were correlated with the insulin resistance index, DI, or HbA1c; These TG values were normalized post-LSG. In conclusion, the glucose tolerance curve measured by the MTT was not normalized in T2DM patients, which was associated with impaired normalization of the DI values in those patients 1-year after the LSG. However, the baseline TG and a fat-induced 2h-TG values were normalized postoperatively. The MTT can be used to assess normalization in postprandial glucose and TG excursions after LSG.

An Inorganic-Organic Hybrid Framework Composed of Polyoxotungstate and Long-Chained Bolaamphiphile.

Surfactants are functional molecules utilized in various situations. The self-assembling property of surfactants enables several molecular arrangements that can be employed to build up nanometer-sized architectures. This is beneficial in the construction of functional inorganic-organic hybrids holding the merits of both inorganic and organic components. Among several surfactants, bolaamphiphile surfactants with two hydrophilic heads are effective, as they have multiple connecting or coordinating sites in one molecule. Here, a functional polyoxotungstate inorganic anion was successfully hybridized with a bolaamphiphile to form single crystals with anisotropic one-dimensional alignment of polyoxotungstate. Keggin-type metatungstate ([H2W12O40]6-, H2W12) was employed as an inorganic anion, and 1,12-dodecamethylenediammonium (C12N2) derived from 1,12-dodecanediamine was combined as an organic counterpart. A simple and general ion-exchange reaction provided a hybrid crystal consisting of H2W12 and C12N2 (C12N2-H2W12). Single crystal X-ray structure analyses revealed a characteristic honeycomb structure in the C12N2-H2W12 hybrid crystal, which is possibly effective for the emergence of conductivity due to the dissociative protons of C12N2.

Nitric oxide bioavailability for red blood cell deformability in the microcirculation: A review of recent progress.

The rheological properties of red blood cells (RBCs) play an important role in their microcirculation. RBCs can elastically deform in response to mechanical forces to pass through narrow vessels for effective gas exchange in peripheral tissues. Decreased RBC deformability is observed in lifestyle-related diseases such as diabetes mellitus, hypercholesterolemia, and hypertension, which are pathological conditions linked to increased oxidative stress and decreased nitric oxide (NO) bioavailability. Redox-sensitive cysteine residues on RBC cytoskeletal proteins, such as α- and ß-spectrins, responsible for membrane flexibility, are affected by prolonged oxidative stress, leading to reversible and irreversible oxidative modifications and decreased RBC deformability. However, endogenously, and exogenously generated NO protects RBC membrane flexibility from further oxidative modification by shielding redox-sensitive cysteine residues with a glutathione cap. Recent studies have shown that nitrate-rich diets and moderate exercise can enhance NO production to increase RBC deformability by increasing the interplay between RBCs and vascular endothelium-mediated NO bioavailability for microcirculation. This review focuses on the molecular mechanism of RBC- and non-RBC-mediated NO generation, and how diet- and exercise-derived NO exert prophylactic effects against decreased RBC deformability in lifestyle-related diseases with vascular endothelial dysfunction.

KPR-5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats.

AIMS: Transient receptor potential melastatin 8 (TRPM8) has a role in the abnormal sensory transduction of the bladder and is involved in the pathophysiology of hyperactivity bladder disorders. The aim of this study is to examine the effects of KPR-5714, a novel and selective TRPM8 antagonist, on voiding dysfunction induced by bladder afferent hyperactivity via mechanosensitive C-fibers in rats. METHODS: The effects of intragastric administration of KPR-5714 on bladder overactivity induced by intravesical instillation of 10 mM ATP were investigated using cystometry in conscious female rats. We examined the effects of oral administration of KPR-5714 on voiding behavior using a metabolic cage in normal male rats and rats with an intratesticular injection of 3% acetic acid. RESULTS: In cystometry measurements, the intercontraction interval was decreased by intravesical ATP instillation. KPR-5714 (0.1, 0.3, and 1 mg/kg) dose-dependently prolonged the shortened intercontraction interval provoked by ATP. In voiding behavior measurements, intratesticular injection of acetic acid decreased the mean voided volume and increased voiding frequency. KPR-5714 (0.1 and 0.3 mg/kg) dose-dependently increased the mean voided volume and decreased voiding frequency without affecting the total voided volume in these rats. However, KPR-5714 (1 and 10 mg/kg) did not influence the voiding behavior in normal rats. CONCLUSION: The present results suggest that KPR-5714 improves voiding dysfunction by inhibiting the enhanced activity of mechanosensitive bladder C-fibers in rats with bladder overactivity and shows no significant change in voiding behavior in normal rats.

Zamamiphidins B and C, Manzamine-Related Alkaloids from an Amphimedon sp. Marine Sponge Collected in Okinawa.

Zamamiphidins B (1) and C (2), two new manzamine-related alkaloids with an unprecedented fused diazahexacyclic ring system, were isolated from an Amphimedon sp. marine sponge collected in Okinawa. The structures of zamamiphidins B (1) and C (2) including the relative configurations were elucidated on the basis of spectroscopic data.

Detection of Bacillus cereus as a causative agent of emetic food poisoning by an unconventional culture procedure.

Bacillus cereus is known to cause two types of food poisoning: emetic and diarrhoeal. Both diseases are usually self-limiting; however, severe cases have been reported, presenting with acute liver failure and encephalopathy, including rarely fatal cases of vomiting. Clinical laboratories do not routinely test for B. cereus in patients with gastrointestinal disease. Therefore, B. cereus causing food poisoning goes undetected. We report a successful isolation of emetic B. cereus from a patient with food poisoning who presented with severe vomiting, fulminant hepatic failure, and acute encephalopathy, by a non-conventional method. Initially, stool specimens from the patients were routinely cultured to identify the causative organisms of food poisoning. No foodborne pathogens were detected in this study. In contrast, additional clinical and epidemiological information strongly suggested food poisoning by emetic B. cereus. Consequently, we allowed Drigalski agar medium smeared with patient stool specimens to stand at room temperature (approximately 25 °C) for 9 days. After 9 days, mixed bacteria grown on the medium were inoculated onto mannitol egg yolk polymyxin (MYP) agar plates, a selective medium for B. cereus. Typical colonies of B. cereus developed on MYP agar plates. The isolated B. cereus had a cereulide-producing genetic locus (ces) gene encoding the emetic toxin cereulide. The method used in this case study was unique. This method is easy to apply after obtaining an additional clinical and epidemiological information, and this method will improve the diagnostic rate of severe B. cereus food poisoning. This will contribute to the advancement of therapeutics in the future.

Effects of a new 75 g glucose- and high fat-containing cookie meal test on postprandial glucose and triglyceride excursions in morbidly obese patients.

A new meal tolerance test (MTT) using a 75 g glucose- and high fat-containing meal was applied to classify glucose intolerance in morbidly obese patients. According to the MTT data, the concordance rate of diagnosis was 82.5% compared to the 75 g oral glucose tolerance test (OGTT) in patients with normal glucose tolerance (NGT, n = 40). In the NGT patients, the insulinogenic index (r = 0.833), Matsuda index (r = 0.752), and disposition index (r = 0.845) calculated from the MTT data were each significantly (p < 0.001) correlated with those derived from the OGTT data. However, in patients with impaired glucose tolerance (IGT, n = 23) or diabetes mellitus (DM, n = 17), the postprandial glucose levels post-MTT were significantly lower than those post-OGTT, without increases in the postprandial insulin levels post-MTT. Thus, the severity of glucose intolerance measured by the MTT was milder than that indicated by the OGTT. Plasma levels of both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) were increased at the postprandial state, but only the GIP levels post-MTT were significantly higher than those post-OGTT. The enhancement of glucose disposal rates in patients with NGT or IGT after the MTT was associated with increased GIP levels. The postprandial hypertriglyceridemia induced by the MTT was associated with insulin resistance, but it was not associated with the impaired insulinogenic index or the disposition index. These results indicate that the new MTT is clinically useful to evaluate both abnormal glucose and triglyceride excursions caused by abnormal insulin sensitivity and secretions of insulin and gut hormones in morbidly obese patients.

Factors influencing school re-entry among adolescents in Kenya.

BACKGROUND: The number of out-of-school children and adolescents has been increasing globally. In sub-Saharan Africa, an estimated 23 million adolescents leave school due to poverty, teenage pregnancy, and unspecified illnesses. The reasons for absenteeism are well-known but the factors involved in the decision to return to school have not been analyzed. This study aimed to identify the factors that promote primary school re-entry among chronic adolescent absentees in rural sub-Saharan Africa. METHODS: Qualitative data were gathered through participant observation, in-depth interviews, and focus group discussions involving nine pupils who returned to school after chronic absenteeism and 140 adult stakeholders in Mbita sub-county, Kenya. Data were analyzed using thematic analysis. RESULTS: The thematic analysis results showed that four factors promoted school re-entry, namely: (1) social norms: "school for a better life"; (2) linkage of community and school; (3) supportive environment; and (4) using discipline to make adolescents serious about their education. CONCLUSIONS: School re-entry among chronic absentees in Mbita sub-county is promoted by both community and school factors. It was observed that social norms regarded an education as a "passport to a better life." Adolescents, teachers, and community leaders view education as a means of improving one's socio-economic status. Two essential elements of health-promoting schools, a supportive environment and a linkage with community, effectively promoted returning to the school among adolescents. The introduction of health-promoting schools was recommended to implement a school re-entry policy in Kenya effectively.

Has the double burden of malnutrition reached pupils in rural western Kenya?

BACKGROUND: Undernutrition and overnutrition have been considered separate challenges caused by the distinct factors in distinct settings. The double burden of malnutrition is defined as the coexistence of both undernutrition and overnutrition, which has now spread globally, especially in low- and middle-income countries. In Kenya, the double burden of malnutrition is present in the capital city but the situation in rural areas currently remains unknown. The aim of this study was therefore to analyze nutritional status in rural Kenya. METHODS: Data from height and weight measurements conducted by teachers in the third term of school year 2013 were collected from primary schools. Teachers were trained by experts before starting the measurements. The Z-scores of height-for-age, weight-for-age, and body mass index-for-age were calculated using AnthroPlus, and nutritional status was defined according to the World Health Organization guidelines. RESULTS: Data analyzed from 7,447 pupils (3,763 boys and 3,684 girls) showed that 12.4% were stunted and 7.8% were underweight among those ≤120 months old, and 11.7% were thin among those >120 months old. Boys were more likely to be stunted than girls. Boys were more likely to be underweight and girls were more likely to be overweight in the older age group. CONCLUSION: The double burden of malnutrition was not found, and undernutrition was still common among schoolchildren in the study area. However, it is important to monitor nutritional status due to adverse effects of rapid urbanization. Height and weight measurements in schools may be useful for monitoring the nutritional status of schoolchildren.

Status of school health programs in Asia: National policy and implementation.

BACKGROUND: The WHO's Health Promoting Schools (HPS) framework is based on an understanding of the reciprocal relationship between health and education, and the need to take a holistic approach to health promotion in schools. We aim to clarify the degree to which the HPS framework is reflected in the national policies of eight target countries and the issues surrounding its successful implementation. METHODS: Date were collected through two expert workshops with participants from eight Asian countries: Cambodia, China, Japan, Korea, Lao PDR, Nepal, the Philippines, and Thailand. In the first workshop, data collected on national policy were mapped against the HPS framework. From this, key issues were identified, and follow-up data collection was conducted in each country for a second workshop. RESULTS: We identified a policy shift toward the HPS framework in six out of the eight countries. Neither Japan nor Korea had changed their national policy frameworks to reflect an HPS approach; however, in the latter, model programs had been introduced at a local level. We identified various barriers to successful implementation, especially in relation to mental health and wellbeing. CONCLUSION: Given the recent shift toward the HPS approach in six out of the eight countries in this study, there is a need to conduct research to assess the impact of this framework on the health and wellbeing of students and school staff. At the same time, we call for more dialog in the context of Japan to explore the possible benefits of introducing the HPS framework into schools.

Investigation on Pathological Aspects, Mode of Transmission, and Tissue Tropism of Antheraea proylei Nucleopolyhedrovirus Infecting Oak Tasar Silkworm.

The temperate oak tasar silkworm, Antheraea proylei, is frequently infested with Antheraea proylei nucleopolyhedrovirus (AnprNPV) causing tiger band disease. This disease is one of the key factors that obstructs production and productivity of oak tasar sericulture. The current study aimed to investigate the pathogenicity of AnprNPV, its mode of transmission, and detection of AnprNPV in different tissues. Transmission electron micrographs of AnprNPV showed single rod-shaped bodies and occlusion derived virus (ODV) enclosed within multiple envelopes. The infecting AnprNPV displayed tissue tropism with higher copy numbers detected in the insect fat body and ovary. The virus was observed to multiply in all developmental stages of the silkworm such as egg, larva, pupa, and moth, confirming its ability to spread throughout the silkworm lifecycle. Baculovirus isolated from infected A. proylei showed cross-infectivity in other Saturniidae wild silkworm species such as Antheraea pernyi, A. frithi, and Samia ricini, widening their probable host range for infection. Baculoviruses generally display a horizontal mode of transmission, mainly through ingestion of occlusion bodies (OBs); however, the present study revealed a trans-ovum vertical mode of transmission in addition to a horizontal mode. The observations made in this study aid a detailed understanding of the tiger band disease and its causative pathogen AnprNPV, which will support future studies and disease management in oak tasar sericulture.

Beneficial Effects of Dietary Nitrite on a Model of Nonalcoholic Steatohepatitis Induced by High-Fat/High-Cholesterol Diets in SHRSP5/Dmcr Rats: A Preliminary Study.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. Endothelial dysfunction caused by hepatic lipotoxicity is an underlying NASH pathology observed in the liver and the cardiovascular system. Here, we evaluated the effect of dietary nitrite on a rat NASH model. Stroke-prone, spontaneously hypertensive 5/Dmcr rats were fed a high-fat/high-cholesterol diet to develop the NASH model, with nitrite or captopril (100 mg/L, each) supplementation in drinking water for 8 weeks. The effects of nitrite and captopril were evaluated using immunohistochemical analyses of the liver and heart tissues. Dietary nitrite suppressed liver fibrosis in the rats by reducing oxidative stress, as measured using the protein levels of nicotinamide adenine dinucleotide phosphate oxidase components and inflammatory cell accumulation in the liver. Nitrite lowered the blood pressure in hypertensive NASH rats and suppressed left ventricular chamber enlargement. Similar therapeutic effects were observed in a captopril-treated rat NASH model, suggesting the possibility of a common signaling pathway through which nitrite and captopril improve NASH pathology. In conclusion, dietary nitrite attenuates the development of NASH with cardiovascular involvement in rats and provides an alternative NASH therapeutic strategy.

Recovering nutrients and rejecting trace organic compounds in human urine by a forward osmosis-membrane distillation (FO-MD) hybrid system.

Urine is a major source of reclaimed water and fertilizer. Urine treatment involves two key processes: the recovery of nutrients and the rejection of trace organic compounds (TOrCs). In this study, we investigated the rejection of TOrCs and the recovery of nutrients in human urine using a seawater-driven forward osmosis and membrane distillation (FO-MD) hybrid system. Three 24 h experiments were conducted at draw solution temperatures of 30, 40, and 50 °C. The average rejection rates of cations, anions, and dissolved organic carbon were more than 93.7% and 79.5% in the FO-MD system and FO side, respectively. Ten types of TOrCs were detected in the feed solution, whereas none were detected in the product water, indicating that the TOrCs were completely rejected. The precipitates, i.e., the recovered nutrients in the FO side, were extremely close to magnesium ammonium phosphate (struvite, MgNH4PO4·6H2O), according to their electron microscopic images, elemental composition, and X-ray diffraction spectra, and it was estimated that approximately 85% of the nutrients in the feed solution were recovered. The rejection and recovery efficiencies were unaffected by the draw solution temperature. These results indicate the potential for the sustainable use of FO-MD-based treatments for human urine.

Lifestyle-mediated nitric oxide boost to prevent SARS-CoV-2 infection: A perspective.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and has seriously threatened public health by causing significant morbidity and mortality. Patients with coronavirus disease (COVID-19) with preexisting endothelial dysfunction caused by aging, diabetes, hypertension, and obesity are at high risk for life-threatening thromboembolic complications. This suggests a possibility that reduced endothelial nitric oxide (NO) production and NO bioavailability could be a common underlying pathology for the progression of COVID-19. Increasingly, evidence from experimental and clinical studies of SARS-CoV-2 infection shows that NO inhibits the pathogenesis of COVID-19, including virus entry into host cells, viral replication, host immune response, and subsequent thromboembolic complications. Restoring NO bioavailability may have the potential to be a preventive or early-treatment option for COVID-19. This review aims to provide in-depth discussion of NO bioavailability to prevent SARS-CoV-2 infection, particularly by focusing on lifestyle factors such as nitrate-rich diets, physical exercise, and nasal breathing, which could be easily performed on a daily basis to boost NO bioavailability.

Nitrite in breast milk: roles in neonatal pathophysiology.

Dietary nitrate has beneficial effects on health maintenance and prevention of lifestyle-related diseases in adulthood by serving as an alternative source of nitric oxide (NO) through the enterosalivary nitrate-nitrite-NO pathway, particularly when endogenous NO generation is lacking due to vascular endothelial dysfunction. However, this pathway is not developed in the early postnatal period due to a lack of oral commensal nitrate-reducing bacteria and less saliva production than in adults. To compensate for the decrease in nitrite during this period, colostrum contains the highest amount of nitrite compared with transitional, mature, and even artificial milk, suggesting that colostrum plays an important role in tentatively replenishing nitrite, in addition to involving a nutritional aspect, until the enterosalivary nitrate-nitrite-NO pathway is established. Increasing evidence demonstrates that breast milk rich in nitrite can be effective in the prevention of neonatal infections and gastrointestinal diseases such as infantile hypertrophic pyloric stenosis and necrotizing enterocolitis, suggesting that breastfeeding is advantageous for newborns at risk, given the physiological role of nitrite in the early postnatal period. IMPACT: The aim of this review is to discuss the physiological roles of nitrite in breast milk and its implications for neonates. Nitrite in breast milk may compensate for the decrease in nitrite during the early neonatal period until the enterosalivary nitrate-nitrite-nitric oxide pathway is established. Breast milk rich in nitrite may be effective in the prevention of neonatal infections and gastrointestinal diseases by providing nitric oxide bioavailability.

Identification of N-acyl-N-indanyl-α-phenylglycinamides as selective TRPM8 antagonists designed to mitigate the risk of adverse effects.

Transient receptor potential melastatin 8 (TRPM8), a temperature-sensitive ion channel responsible for detecting cold, is an attractive molecular target for the treatment of pain and other disorders. We have previously discovered a selective TRPM8 antagonist, KPR-2579, which inhibited bladder afferent hyperactivity induced by acetic acid instillation into the bladder. However, additional studies have revealed potential adverse effects with KPR-2579, such as the formation of a reactive metabolite, CYP3A4 induction, and convulsions. In this report, we describe the optimization of α-phenylglycinamide derivatives to mitigate the risk of these adverse effects. The optimal compound 13x exhibited potent inhibition against icilin-induced wet-dog shakes and cold-induced frequent voiding in rats, with a wide safety margin against the potential side effects.