Intrauterine Inflammation, Excessive Fetal Growth and Respiratory Morbidities in Moderate-To-Late Preterm Neonates.

INTRODUCTION: Respiratory morbidities in neonates are often progressive and life-threatening, and its early prediction is crucial. Intrauterine inflammation is one of the key control variables of respiratory morbidities in both very preterm and term neonates; however, little is known about its effects in the remaining group of moderate-to-late preterm neonates born between 32+0 and 36+6 weeks of gestation. This study aimed to confirm whether intrauterine inflammation is associated with respiratory morbidities in moderate-to-late preterm neonates. METHODS: A single-center retrospective observational study was conducted in neonates born between 32+0 and 34+6 weeks of gestation between April 2013 and March 2018. The correlation between respiratory morbidities (defined as a requirement for invasive mechanical ventilation longer than the median duration of 3 days) and intrauterine inflammation was assessed using multivariable logistic regression analysis. RESULTS: The study population comprised 242 neonates born at 33.7 ± 0.8 weeks of gestation and weighing 1,936 ± 381 g. The multivariable model to predict the outcome comprised respiratory distress syndrome (odds ratio [OR]: 9.1; 95% confidence interval [CI]: 3.7-22.5; p < 0.001), lower gestational age (per week; OR: 0.5; 95% CI: 0.3-0.8; p < 0.005), higher birth-weight z-score (OR: 1.6; 95% CI: 1.2-2.2; p < 0.005), lower cord blood pH (per 0.10; OR: 0.5; 95% CI: 0.3-0.7; p < 0.005), and chorioamnionitis (OR: 2.8; 95% CI: 1.1-7.2; p < 0.05). CONCLUSION: Together with the incidence of respiratory distress syndrome and gestational age, chorioamnionitis and high birth-weight z-scores were associated with an increased incidence of respiratory morbidities in moderate-to-late preterm neonates. The deleterious impact of intrauterine inflammation on the lungs may be common in neonates of virtually all gestational ages. Traditional admission policy of neonatal intensive care units based on a threshold birth-weight, may leave a group of neonates without close observation despite their increased risks for respiratory morbidities.

Primordial Germ Cell Cryopreservation and Revival of Drosophila Strains.

Drosophila strains must be maintained by the frequent transfer of adult flies to new vials. This carries a danger of mutational deterioration and phenotypic changes. Development of an alternative method for long-term preservation without such changes is therefore imperative. Despite previous successful attempts, cryopreservation of Drosophila embryos is still not of practical use because of low reproducibility. Here, we describe a protocol for primordial germ cell (PGC) cryopreservation and strain revival via transplantation of cryopreserved PGCs into agametic Drosophila melanogaster (D. melanogaster) host embryos. PGCs are highly permeable to cryoprotective agents (CPAs), and developmental and morphological variation among strains is less problematic than in embryo cryopreservation. In this method, PGCs are collected from approximately 30 donor embryos, loaded into a needle after CPA treatment, and then cryopreserved in liquid nitrogen. To produce donor-derived gametes, the cryopreserved PGCs in a needle are thawed and then deposited into approximately 15 agametic host embryos. A frequency of at least 15% fertile flies was achieved with this protocol, and the number of progeny per fertile couple was always more than enough to revive the original strain (the average progeny number being 77.2 ± 7.1), indicating the ability of cryopreserved PGCs to become germline stem cells. The average number of fertile flies per needle was 1.1 ± 0.2, and 9 out of 26 needles produced two or more fertile progeny. It was found that 11 needles are enough to produce 6 or more progeny, in which at least one female and one male are likely included. The agametic host makes it possible to revive the strain quickly by simply crossing newly emerged female and male flies. In addition, PGCs have the potential to be used in genetic engineering applications, such as genome editing.

Alcohol and caffeine synergistically induce spontaneous ventricular tachyarrhythmias: ameliorated with dantrolene treatment.

Background: Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase cardiac arrhythmia risk. However, it is unknown whether alcohol and caffeine co-consumption can synergistically enhance cardiac arrhythmogenesis. Objective: The study sought to investigate whether caffeine and binge drinking synergistically affect cardiac arrhythmogenesis. Methods: A binge drinking rat model (alcohol 2 g/kg, intraperitoneal, every other day for 3 times) was used. Rats (4 months old, both sexes) were randomized into the following 4 groups: binge alcohol-only group (A) (n = 8), nonalcohol, caffeine-only (60 mg/kg, intraperitoneal) group (C) (n = 8), binge alcohol plus caffeine group (A+C) (n = 8), and binge alcohol + caffeine + dantrolene group (A+D) (n = 7, treated with dantrolene 10 mg/kg before each alcohol injection). We also investigated whether alcohol induces Ca2+ sparks and dantrolene treatment attenuates alcohol-induced Ca2+ leak in ventricular myocytes. Results: No arrhythmia was induced with caffeine alone (group C, n = 0 of 8) or alcohol alone (group A, n = 0 of 8). However, alcohol + caffeine induced spontaneous ventricular tachyarrhythmias in all rats (group A+C, n = 8 of 8; P < .001 vs group C or A). Dantrolene prevented ventricular tachyarrhythmia induction in all 7 rats (group A+D, n = 0 of 7; P < .001 vs group A+C). In isolated ventricular myocytes, alcohol significantly increased Ca2+ sparks and dantrolene treatment reduced alcohol-induced Ca2+ sparks. Conclusion: Co-consumption of caffeine and binge drinking synergistically promote spontaneous ventricular tachyarrhythmias in rats. Dantrolene treatment can decrease alcohol-enhanced Ca2+ sparks in vitro and prevented alcohol and caffeine induced ventricular tachyarrhythmias in vivo.

Bioproduction of n-3 polyunsaturated fatty acids by nematode fatty acid desaturases and elongase in Drosophila melanogaster.

n-3 polyunsaturated fatty acids (n-3 PUFAs), including α-linolenic acid and eicosapentaenoic acid (EPA), are essential nutrients for vertebrates including humans. Vertebrates are n-3 PUFA-auxotrophic; hence, dietary intake of n-3 PUFAs is required for their normal physiology and development. Although fish meal and oil have been utilized as primary sources of n-3 PUFAs by humans and aquaculture, these traditional n-3 PUFA sources are expected to be exhausted because of the increasing consumption requirements of humans. Hence, it is necessary to establish alternative n-3 PUFA sources to reduce the gap between the supply and demand of n-3 PUFAs. Here, we investigated whether insects, which are considered as a novel source of essential nutrients, could store n-3 PUFAs by the forced expression of n-3 PUFA biosynthetic enzymes. We utilized Drosophila as an insect model to generate transgenic strains expressing Caenorhabditis elegans PUFA biosynthetic enzymes and examined their effects on the proportion of fatty acids. The ubiquitous expression of methyl-end desaturase FAT-1 prominently enhanced the proportions of α-linolenic acid, indicating that FAT-1 is useful for metabolic engineering to fortify α-linolenic acid in insect. Furthermore, the ubiquitous expression of nematode front-end desaturases (FAT-3 and FAT-4), PUFA elongase (ELO-1), and FAT-1 led to EPA bioproduction. Hence, nematode PUFA biosynthetic genes may serve as powerful genetic tools for enhancing the proportion of EPA in insects. This study represents the first step toward the establishment of n-3 PUFA-producing insects.

Short-term effects of the chemical components of fine particulate matter on pulmonary function: A repeated panel study among adolescents.

The effects of the chemical components of fine particulate matter (PM2.5) have been drawing attention. However, information regarding the impact of low PM2.5 concentrations is limited. Hence, we aimed to investigate the short-term effects of the chemical components of PM2.5 on pulmonary function and their seasonal differences in healthy adolescents living on an isolated island without major artificial sources of air pollution. A panel study was repeatedly conducted twice a year for one month every spring and fall from October 2014 to November 2016 on an isolated island in the Seto Inland Sea, which has no major artificial sources of air pollution. Daily measurements of peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) were performed in 47 healthy college students, and the concentrations of 35 chemical components of PM2.5 were analyzed every 24 h. Using a mixed-effects model, the relationship between pulmonary function values and concentrations of PM2.5 components was analyzed. Significant associations were observed between several PM2.5 components and decreased pulmonary function. Among the ionic components, sulfate was strongly related to decreases in PEF and FEV1 (-4.20 L/min [95 % confidence interval (CI): -6.40 to -2.00] and - 0.04 L [95 % CI: -0.05 to -0.02] per interquartile range increase, respectively). Among the elemental components, potassium induced the greatest reduction in PEF and FEV1. Therefore, PEF and FEV1 were significantly reduced as the concentrations of several PM2.5 components increased during fall, with minimal changes observed during spring. Several chemical components of PM2.5 were significantly associated with decreased pulmonary function among healthy adolescents. The concentrations of PM2.5 chemical components differed by season, suggesting the occurrence of distinct effects on the respiratory system depending on the type of component.

Identification of novel candidate genes leading to sex differentiation in primordial germ cells of Drosophila.

Germline sex determination and differentiation are pivotal processes in reproduction. In Drosophila, sex determination of the germline occurs in primordial germ cells (PGCs), and the sex differentiation of these cells is initiated during embryogenesis. However, the molecular mechanism initiating sex differentiation remains elusive. To address this issue, we identified sex-biased genes using RNA-sequencing data of male and female PGCs. Our research revealed 497 genes that were differentially expressed more than twofold between sexes and expressed at high or moderate levels in either male or female PGCs. Among these genes, we used microarray data of PGCs and whole embryos to select 33 genes, which are predominantly expressed in PGCs compared to the soma, as candidate genes contributing to sex differentiation. Of 497 genes, 13 genes that were differentially expressed more than fourfold between sexes were also selected as candidates. Among the 46 (33 + 13) candidates, we confirmed the sex-biased expression of 15 genes by in situ hybridization and quantitative reverse transcription-polymerase chain reaction (qPCR) analysis. Six and nine genes were predominantly expressed in male and female PGCs, respectively. These results represent a first step toward elucidating the mechanisms that initiate sex differentiation in the germline.

Protein-Balanced Dietary Habits Benefit Cognitive Function in Japanese Older Adults.

Since daily dietary habits can affect cognitive function, dietary patterns such as the Mediterranean-DASH Intervention for Neurodegenerative Delay diet have been proposed as interventions to slow cognitive decline. However, because dietary habits vary widely among different food cultures, it is necessary to establish dietary pattern intervention methods that are appropriate for each population. Therefore, in this study, the dietary patterns of elderly Japanese individuals were classified using cluster analysis, and their relationship with cognitive function was investigated. We then modeled the dietary patterns and applied them to another cohort of elderly Japanese individuals to determine whether differences in dietary patterns could predict cognitive decline. One hundred and fifty older adults ≥ 65 years of age in the community were recruited. Their daily food intake and cognitive function were measured using the brief-type self-administered diet history questionnaire and Montreal Cognitive Assessment, respectively. K-means cluster analysis identified a high-carbohydrate (HC) dietary pattern with high cereal intake and a protein-balanced (PB) dietary pattern with high intake of legumes, vegetables, seafood, meat, and eggs. Cognitive function was significantly higher in the PB group than in the HC group. Furthermore, to classify the new data into HC and PB patterns, a classification model was created by discriminant analysis using food groups with significantly different intakes among dietary patterns. Next, we recruited 267 new older adults ≥ 65 years of age and measured food intake and cognitive function assessed using the memory performance index score. Individuals with cognitive decline were identified and their detailed cognitive functions were assessed using the neurocognitive index score. Cognitive function was significantly impaired in the HC pattern in both the general elderly and cognitively impaired cohorts. These findings suggest that a dietary pattern of low carbohydrate and high protein intake is associated with good cognitive function in elderly Japanese individuals. Classification by these dietary patterns can predict cognitive reservation in community-dwelling older adults.

Lysosomal dysfunction in diabetic cardiomyopathy.

Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.

Metformin Inhibits Autophagy, Mitophagy and Antagonizes Doxorubicin-Induced Cardiomyocyte Death.

The antidiabetic drug metformin has been shown to reduce cardiac injury under various pathological conditions, including anticancer drug doxorubicin (DOX)-induced cardiotoxicity, which makes metformin a prime candidate for repurposing. However, the mechanisms that mediate the cardioprotective effects of metformin remain highly controversial. In this study, we tested a prevailing hypothesis that metformin activates autophagy/mitophagy to reduce DOX cardiotoxicity. FVB/N mice and H9C2 cardiac myoblasts were treated with metformin, respectively. Autophagy/mitophagy was determined by Western blot analysis of microtubule-associated protein light chain 3, form-II (LC3-II), a well-established marker of autophagic vesicles. Although metformin had minimal effects on basal LC3-II levels, it significantly inhibited the accumulation of LC3-II levels by the lysosomal protease inhibitors pepstatin A and E64d in both total cell lysates and mitochondrial fractions. Also, dual fluorescent autophagy/mitophagy reporters demonstrated that metformin slowed the degradation rate of autophagic cargos or mitochondrial fragments in the lysosomes. These surprising results suggest that metformin inhibits rather than stimulates autophagy/mitophagy, sharply contrasting the popular belief. In addition, metformin diminished DOX-induced autophagy/mitophagy as well as cardiomyocyte death. Together, these results suggest that the cardioprotective effects of metformin against DOX cardiotoxicity may be mediated by its ability to inhibit autophagy and mitophagy, although the underlying molecular mechanisms remain to be determined.

Influence of Intrauterine Inflammation, Delivery, and Postnatal Feeding on the Temporal Changes of Serum Alpha 1 Acid Glycoprotein Levels in Extremely-Low-Birth-Weight Infants.

Infection remains the primary cause of death in extremely-low-birth-weight infants (ELBWIs). Alpha 1 acid glycoprotein (α1AG), an acute-phase protein, has been shown to be elevated in sporadic cases of septic ELBWIs prior to abnormal clinical signs. To delineate the roles of inflammation, delivery, and feeding in postnatal α1AG changes in ELBWIs, 75 ELBWIs of 26.5 ± 2.2 weeks of gestation born between May 2011 and August 2017 were retrospectively studied. The dependence of α1AG levels obtained on days 0−5 on the clinical variables was examined by incorporating interactions with age, followed by estimations of regression coefficients between clinical variables and α1AG levels at the early and late postnatal ages, defined by their standard deviation. Chorioamnionitis (p < 0.001), funisitis (p = 0.045), vaginal delivery (p = 0.025), enteral feeding (p = 0.022), and probiotics (p = 0.005) were associated with early α1AG elevations. Hypertensive disorder of pregnancy (p < 0.001) and gestational age (p = 0.001) were associated with late α1AG elevation; premature rupture of membranes (p < 0.001), funisitis (p = 0.021), body weight z-scores (p < 0.001), and enteral feeding (p = 0.045) were associated with late α1AG reduction. Postnatal α1AG changes in ELBWIs were associated with variables representative of age, growth, delivery, inflammation, and enteral feeding, potentially reflecting the process of sensitization to extrinsic microbes in utero, at birth, and thereafter.

Effects of Lactiplantibacillus plantarum OLL2712 on Memory Function in Older Adults with Declining Memory: A Randomized Placebo-Controlled Trial.

The use of probiotics is expected to be an intervention in neurodegenerative conditions that cause dementia owing to their ability to modulate neuroinflammatory responses via the microbiome-gut-brain axis. Therefore, we selected Lactiplantibacillus plantarum OLL2712 (OLL2712), the optimal anti-inflammatory lactic acid bacteria strain with high IL-10-inducing activity in immune cells, and aimed to verify its protective effects on memory function in older adults. A 12-week, randomized, double-blind, placebo-controlled trial was performed with older adults over the age of 65 years with declining memory. The participants consumed either powder containing heat-treated OLL2712 cells or placebo. Memory function was assessed using a computer-assisted cognitive test, Cognitrax. Daily dietary nutrient intake was assessed using the Brief-type Self-administered Diet History Questionnaire (BDHQ). The composition of the gut microbiota was analyzed by fecal DNA extraction and 16S rDNA sequencing. Data from 78 participants who completed the entire procedure were analyzed, and significant improvements in composite memory and visual memory scores were observed in the active group, after accounting for the effect of daily nutritional intake (p = 0.044 and p = 0.021, respectively). In addition, the active group had a lower abundance ratio of Lachnoclostridium, Monoglobus, and Oscillibacter genera, which have been reported to be involved in inflammation. The present study suggests that OLL2712 ingestion has protective effects against memory function decline in older adults.

Stabilizing Cardiac Ryanodine Receptor With Dantrolene Treatment Prevents Binge Alcohol-Enhanced Atrial Fibrillation in Rats.

ABSTRACT: Binge drinking is a risk factor for cardiac arrhythmias, known as the holiday heart syndrome. Atrial fibrillation (AF) is the most frequently diagnosed arrhythmia in this condition. Recent reports indicated that cardiac ryanodine receptor (RyR2) dysfunction and Ca 2+ leak contribute to alcohol-enhanced AF. In this study, we investigated whether stabilizing RyR2 with dantrolene treatment can prevent alcohol-enhanced AF in rats. A binge drinking rat model was established with alcohol (2 g /kg, IP) delivered once every other day for 4 times. The study consisted of following 3 groups: control group (n = 9), binge alcohol group (n = 10), and binge alcohol + dantrolene (A+D) group (dantrolene, 10 mg/kg, IP before each alcohol injection, n = 9). Echocardiography, left ventricular hemodynamics, in vivo atrial electrophysiology and AF inducibility test, RyR2 phosphorylation level, and blood norepinephrine level were studied 24 hours after the last injection. Ca 2+ leak in isolated atrial myocytes from control and binge alcohol rats was examined. Binge alcohol significantly increased AF inducibility (1/9 in control vs. 8/9 in binge alcohol group, P < 0.05) and AF duration. Dantrolene treatment significantly reduced both AF inducibility (2/9 in dantrolene group, P < 0.05) and AF duration. Binge alcohol significantly increased Ca 2+ leak in isolated atrial myocytes, which was reduced by dantrolene treatment. Blood norepinephrine,7 RyR2 phosphorylation level, cardiac echocardiography, and left ventricular hemodynamics were not significantly affected 24 hours after binge drinking. In conclusion, stabilizing RyR2 with dantrolene treatment significantly attenuated binge drinking-enhanced AF, suggesting that therapeutic strategies stabilizing RyR2 could be a preventive measure to blunt binge drinking-enhanced AF arrhythmogenesis.

Predictivity of acute kidney injury risk scores for late kidney injury in patients with chronic coronary syndrome.

Late rather than acute kidney injury after percutaneous coronary intervention (PCI) has been recently recognized as a predictor of future adverse events in patient with coronary artery disease. The risk-predicting models for acute kidney injury reported by Mehran et al., Bartholomew et al., and Tsai et al. were derived from a large cohort and externally validated, although the applicability of these models for predicting late kidney injury is unknown. A total of 327 patients undergoing elective PCI procedures were included. We calculated the three scores and tested their diagnostic ability for predicting late kidney injury (> 6 months after PCI), defined as an increase in creatinine levels ≥ 0.3 mg/dl or ≥ 50% from baseline. During the median follow-up period of 28 months, 27 (8.3%) patients had late kidney injury. All three scores significantly predicted late kidney injury, among which the score by Tsai et al. had a better diagnostic ability (area under the curve 0.83, best cut-off value 14, p < 0.001). With the best cut-off value, patients with Tsai score ≥ 14 had a significantly higher rate of late kidney injury than their counterpart (27.4% vs. 2.8%, p < 0.001). In conclusion, established risk scores for acute kidney injury may be useful for predicting late kidney injury after PCI in patients with chronic coronary syndrome.

Biosynthesis of S-adenosyl-methionine enhances aging-related defects in Drosophila oogenesis.

Tissue aging is a major cause of aging-related disabilities and a shortened life span. Understanding how tissue aging progresses and identifying the factors underlying tissue aging are crucial; however, the mechanism of tissue aging is not fully understood. Here we show that the biosynthesis of S-adenosyl-methionine (SAM), the major cellular donor of methyl group for methylation modifications, potently accelerates the aging-related defects during Drosophila oogenesis. An aging-related increase in the SAM-synthetase (Sam-S) levels in the germline leads to an increase in ovarian SAM levels. Sam-S-dependent biosynthesis of SAM controls aging-related defects in oogenesis through two mechanisms, decreasing the ability to maintain germline stem cells and accelerating the improper formation of egg chambers. Aging-related increases in SAM commonly occur in mouse reproductive tissue and the brain. Therefore, our results raise the possibility suggesting that SAM is the factor related to tissue aging beyond the species and tissues.

Endoscopic application of novel, infection-free, advanced hemostatic material: Its usefulness to upper gastrointestinal oozing.

Background: Self-assembling peptides (TDMs) comprise synthetic amphipathic peptides that immediately react to changes in pH and/or inorganic salts to transform into a gelatinous state. The first generation of these peptides (TDM-621) is currently used as a hemostatic agent in Europe. However, TDM-621 exhibits slow gel-formation and low retention capabilities on tissue surfaces. The second generation (TDM-623) was therefore developed to encourage faster gel-formation and better tissue-sealing capabilities. Aim: The aim of this study was to verify the efficacy of TDM-623 in terms of its hemostatic effect in endoscopic surgery. Materials and methods: Evaluation of the hemostatic effect in endoscopic surgery (animal study) was performed using eight porcine in spine position. Following systemic heparinization, we established a "bleeding model" by endoscopic grasping forceps on the anterior walls of the stomach and duodenum. In the hemostasis method, an endoscope with a distal hood was brought into contact with the bleeding point, and 1 ml TDM-623 was applied to the wound. After TDM-623 gelation, the endoscope was removed, and the acute hemostatic effect (after 2 min) was confirmed. Result: In the endoscopic bleeding model, 17 of the 23 cases (74%) showed complete hemostatic effects on the anterior wall of the stomach, and 18 of the 20 cases (80%) on the anterior wall of the duodenum, respectively. None of the applied gels were displaced from the anterior walls of the stomach and duodenum. Conclusion: The new self-assembling peptide (TDM-623) showed high hemostatic effects. TDM-623 had potential usefulness for upper gastrointestinal endoscopic surgery.

[Lung Transplantation at a Low Volume Center].

The number of lung transplantation performed in Japan is extremely low compared to other countries, whereas we have 10 facilities certified as cadaveric lung transplantation in Japan, meaning that there are low volume centers. By August 2021, we performed lung transplantation in 21 cases for 12 years, therefore, our facility should be considered as low volume center. Surgical outcomes at low volume centers are generally considered poor. However, the overall five-year survival rate of total cases was 84.8%, and that of cadaveric cases was 94.4% in our hospital. It was better than the average of about 73% of all facilities in Japan. These data suggested that the accreditation system in Japan is functioning well. On the other hand, there may be a disparity between facilities. At our facility, we are actively performing inverted lung transplantation so as not to lose the opportunity for transplantation, and we have performed it in three cases so far and have achieved good results.

Unusual presentation of acute encephalopathy with biphasic seizures and late reduced diffusion in Miller-Dieker syndrome.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a unique subtype of acute encephalopathy that occurs in children. A girl aged 2 years and 8 months with Miller-Dieker syndrome (MDS) was admitted for status epilepticus and high fever. Brain MRI performed on the third day postadmission showed abnormally high intensities in the subcortical white matter on diffusion-weighted images. Acute encephalitis/encephalopathy was diagnosed based on the electroencephalography (EEG) findings of diffuse high-voltage delta waves. Six days postadmission, frequent apnoeic episodes were observed, with oxygen desaturation due to cluster seizures. Subclinical seizures were found on amplitude-integrated EEG (aEEG). The disturbance of consciousness was difficult to recognise because of severe developmental disabilities due to MDS. EEG aids in the evaluation of consciousness, and aEEG can be helpful in monitoring and controlling subclinical seizures in the biphasic phase of AESD, especially in patients with underlying neurological disorders.

Demystifying the Relationship Between Metformin, AMPK, and Doxorubicin Cardiotoxicity.

Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but its long-term use can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity and concurrently enhance its antitumor efficacy would be of great clinical value. In this respect, the classical antidiabetic drug metformin (MET) has stood out, appearing to have both antitumor and cardioprotective properties. MET is proposed to achieve these beneficial effects through the activation of AMP-activated protein kinase (AMPK), an essential regulator of mitochondrial homeostasis and energy metabolism. AMPK itself has been shown to protect the heart and modulate tumor growth under certain conditions. However, the role and mechanism of the hypothesized MET-AMPK axis in DOX cardiotoxicity and antitumor efficacy remain to be firmly established by in vivo studies using tumor-bearing animal models and large-scale prospective clinical trials. This review summarizes currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. It also highlights the emerging evidence suggesting distinct roles of the AMPK subunit isoforms in mediating the functions of unique AMPK holoenzymes composed of different combinations of isoforms. Moreover, the review provides a perspective regarding future studies that may help fully elucidate the relationship between MET, AMPK and DOX cardiotoxicity.

Congenital nephrogenic diabetes insipidus presenting as osmotic demyelination syndrome in infancy: A case report.

RATIONALE: Almost 90% of congenital nephrogenic diabetes insipidus (NDI) cases are caused by mutations in the arginine vasopressin receptor 2 gene, which has X-linked recessive inheritance. Although NDI is commonly diagnosed in early infancy based on its characteristic findings, clinical diagnosis can be delayed when no other family members have been diagnosed with NDI because several findings of NDI are nonspecific. PATIENT CONCERNS: A 3-month-old boy diagnosed with NDI presenting with osmotic demyelination syndrome (ODS) was admitted for poor weight gain after birth and poor feeding during the week prior to admission. DIAGNOSIS: On admission, the initial blood examination showed hypernatremia (158 mmol/L), and treatment with intravenous fluids over the next 2 days further elevated the serum sodium level (171 mmol/L). After admission, polyuria was recognized, and polyuria in his grandmother and mother since childhood without a diagnosis of NDI was found. Magnetic resonance imaging showed multifocal, symmetrical lesions, including the lateral pons, on diffusion- and T2-weighted imaging, which led to a diagnosis of ODS. INTERVENTION: The infusion was stopped, and the patient was fed milk diluted 2-fold with water. OUTCOMES: The serum sodium level gradually decreased to 148 mmol/L over the course of 1 week. Low-sodium milk was started at 4 months of age and maintained a serum sodium level of approximately 140 mmol/L, which was within the normal range. The developmental quotient was 94 at 4 years of age. LESSONS: ODS is an encephalopathy resulting from extreme fluctuations in serum sodium concentration and plasma osmolality. ODS due to hypernatremia has been reported in several patients, although it usually occurs during rapid correction of hyponatremia. Consequences of the central nervous system are a critical complication of NDI that affects prognosis. These consequences can be avoided with treatment. Early blood examination or polyuria in the patient, mother, or another family member and hypernatremic dehydration with good urine output should lead to an early diagnosis and prevent central nervous system consequences.

Dual role of Ovol2 on the germ cell lineage segregation during gastrulation in mouse embryogenesis.

In mammals, primordial germ cells (PGCs), the origin of the germ line, are specified from the epiblast at the posterior region where gastrulation simultaneously occurs, yet the functional relationship between PGC specification and gastrulation remains unclear. Here, we show that OVOL2, a transcription factor conserved across the animal kingdom, balances these major developmental processes by repressing the epithelial-to-mesenchymal transition (EMT) that drives gastrulation and the upregulation of genes associated with PGC specification. Ovol2a, a splice variant encoding a repressor domain, directly regulates EMT-related genes and, consequently, induces re-acquisition of potential pluripotency during PGC specification, whereas Ovol2b, another splice variant missing the repressor domain, directly upregulates genes associated with PGC specification. Taken together, these results elucidate the molecular mechanism underlying allocation of the germ line among epiblast cells differentiating into somatic cells through gastrulation. This article has an associated 'The people behind the papers' interview.