Furosemide­induced eradication of myeloblasts via the inhibition of tumor necrosis factor­α expression in a patient with acute biphenotypic leukemia: A case report.

The present study reports the potential of furosemide therapeutic activity in acute myeloid leukemia. A 26-year-old man with acute biphenotypic leukemia was treated with furosemide for suspected pulmonary edema, which was later deemed to be an infiltration of leukemia cells. Notably, the myeloblast population was rapidly eliminated during furosemide therapy. Bone marrow specimens biopsied at different time points were used for immunohistochemical analysis of the expression levels of tumor necrosis factor-α (TNF-α) and its two receptors, TNF-α receptors 1 and 2. The expression of TNF-α and its receptors in the bone marrow was markedly suppressed by furosemide, along with the elimination of the myeloblasts. Thus, it was hypothesized that the growth of myeloblasts in the patient depended on autocrine and/or paracrine TNF-α stimulation, whereas furosemide disrupted this positive feedback loop. Therefore, furosemide is suggested as an effective therapeutic agent for acute myeloid leukemia, at least as an adjunct to standard chemotherapy and gene-targeted therapy.

Bioactive Properties of Enzymatic Gelatin Hydrolysates Based on In Silico, In Vitro, and In Vivo Studies.

This current study aims to analyze the potential bioactivities possessed by the enzymatic hydrolysates of commercial bovine, porcine, and tilapia gelatins using bioinformatics in combination with in vitro and in vivo studies. The hydrolysate with superior inhibition of angiotensin converting enzyme (ACE) activity was used to treat the D-galactose (DG)-induced amnesic mice. In silico digestion of the gelatins led to the identification of peptide sequences with potential antioxidant, ACE-inhibitory, and anti-amnestic properties. The results of in vitro digestion revealed that the <1 kDa peptide fraction of porcine gelatin hydrolysate obtained after 1 h digestion with papain (PP) (PP1, <1 kDa) potently inhibited ACE, acetylcholinesterase, and prolyl endopeptidase activities at 87.42%, 21.24%, and 48.07%, respectively. Administering the PP1 to DG-induced amnesic mice ameliorated the spatial cognitive impairment and Morris water maze learning abilities. The dentate area morphology in the PP1-treated mice was relatively similar to the control group. In addition, PP1 enhanced the antioxidant capacity in the DG-induced amnesic mice. This study suggests that PP1 could serve as a potential treatment tool against oxidative stress, hypertension, and neurodegenerative diseases.

Hyalinizing clear cell carcinoma in the nasopharynx: A case report and literature review.

RATIONALE: Hyalinizing clear cell carcinoma (HCCC) arising from a minor salivary gland is a rare malignant neoplasm. Most HCCC has been reported in the palate and tongue base, and only rarely in the nasopharynx. Here, we report a rare case of nasopharyngeal HCCC. PATIENT CONCERNS: A 44-year-old male who complained of otorrhea and aural fullness for 5 years was found to have a nasopharyngeal mass. DIAGNOSES: HCCC by fluorescence in situ hybridization analysis. INTERVENTIONS: Surgical resection plus concurrent chemotherapy and radiation therapy were administered. OUTCOMES: The patient recovered well with symptoms improved at postoperative follow-up. LESSONS: HCCC should be included in the differential diagnosis of nasopharyngeal mass. Overall, the prognosis of HCCC is positive after tumor resection and adequate management.

Protein identification and potential bioactive peptides from pumpkin (Cucurbita maxima) seeds.

Pumpkin is an economically important crop all over the world. Approximately, 18%-21% of pumpkins, consisting of peels and seeds by-products, are wasted during processing. In addition, the seeds are rich in protein and have the potency of bioactive peptide production. This study aims to recognize the proteins and investigate the potential bioactive peptides from pumpkin (Cucurbita maxima) seeds. Pumpkin seeds were subjected to hot air drying (HAD) at 55°C for 12 h and freeze-drying (FD) at -80°C for 54 h before they were powdered, analyzed, and precipitated by isoelectric point to obtain pumpkin seed protein isolates (PSPI). PSPI comprised 11S globulin subunit beta, 2S seed storage albumin, and chaperonin CPN60-1. To generate hydrolysate peptides, PSPI was hydrolyzed using papain, pepsin, and bromelain. FD group pepsin hydrolysates had the highest peptide content of 420.83 mg/g. ACE inhibition and DPP-IV inhibition activity were analyzed for each enzymatic hydrolysate. The pepsin hydrolyzed sample exhibited the highest ACE inhibition of 70.26%, and the papain hydrolyzed sample exhibited the highest DPP-IV inhibition of 30.51%. The simulated gastrointestinal digestion (SGID) conducted by pepsin and pancreatin increased ACE inhibitory activity from 76.93% to 78.34%, and DPP-IV inhibited activity increased from 58.62% to 77.13%. Pepsin and papain hydrolysates were fractionated using ultrafiltration to measure ACE and DPP-IV inhibition activity. The highest free radical scavenging abilities were exhibited by the <1 kDa hydrolysate fractions with 78.34% ACE inhibitory activities and 79.55% DPP-IV inhibitory activities. This research revealed that pumpkin seeds had the potency to produce bioactive peptides.

Streptococcus thermophilus iHA318 Improves Dry Eye Symptoms by Mitigating Ocular Surface Damage in a Mouse Model.

Dry eye is a complicated ocular surface disease that causes discomfort, visual disturbance, and frequently observed ocular surface damage. Emerging hypotheses suggest probiotics may help relieve dry eye symptoms by modulating inflammation and oxidative stress. This study aimed to investigate the therapeutic effects of Streptococcus thermophilus iHA318 probiotics on dry eye using in vitro assays and an in vivo murine model of ultraviolet B (UVB) radiation-induced dry eye. In vitro analyses revealed that S. thermophilus iHA318® exhibited antioxidant activity and anti-inflammatory effects by inhibiting reactive oxygen species production and suppressing inflammatory cytokines. For the in vivo study, female ICR mice were assigned to normal control, UVB-induced dry eye, and UVB+iHA318 treatment groups. UVB exposure significantly decreased tear volume and tear film breakup time (TBUT) compared to normal controls. Supplementation with S. thermophilus iHA318® via oral gavage markedly improved tear production and TBUT on day 7 post-UVB exposure. Ocular surface photography demonstrated improved gradings of corneal opacity, smoothness, and lissamine green staining in the iHA318 group versus the UVB group. Topographical analysis further revealed improvement in the UVB-induced corneal irregularities by iHA318 treatment. Collectively, these results indicate that S. thermophilus iHA318 exerts a protective effect against dry eye symptoms by mitigating oxidative stress and inflammation, thereby preserving tear film stability and ocular surface integrity. This probiotic strain represents a promising therapeutic approach for managing dry eye syndrome.

Characterization of Functional Ingredients Extracted with Ethanol Solvents from Ponkan (Citrus reticulata) By-Products Using the Microwave Vacuum Drying Method Combined with Ultrasound-Assisted Extraction.

For this study, microwave vacuum drying (MVD) was combined with ultrasound-assisted extraction to compare the effects of different ethanol volumes on ponkan extract and to evaluate the total phenolic content (TPC), total flavonoid content (TFC), and total ascorbic acid content (TAAC). High-performance liquid chromatography with photodiode array detection (HPLC-PDA) was used to analyze the flavanone contents and antioxidant activity of ponkan (Citrus reticulata) peels. The experimental results showed that the TPC and TFC increase with ethanol volume. Ethanol extraction (75%) showed significant advantages by increasing the TPC to 17.48 mg GAE/g (DW) and the TFC to 2.96 mg QE/g (DW) of ponkan extract and also exhibited the highest antioxidant activity. The TAAC improved along with increased water content. Water extraction showed the highest content (13.07 mg VitC/100 g, DW). The hesperidin content analyzed by HPLC-PDA was 102.95-622.57 mg/100 g (DW), which was the highest among the flavanones. Then, the ethanol insoluble residue extracts were taken from the pectin with four different solvents, evaluating TPC, TFC, and antioxidant activity. The TPC, TFC, and antioxidant capacity of pectin are significantly lower than those of the peels. Combining MVD and 75% ethanol with ultrasound-assisted extraction in the pre-treatment process can effectively eliminate polyphenols, flavonoids, and other compounds, thus enabling the extraction of high-methoxyl pectin. The total dietary fiber (TDF) content of MVD ponkan by-products was 25.83%. Ponkan by-products have the potential for the future development of functional foods and supplements.

Missing data imputation using classification and regression trees.

Background: Missing data are common when analyzing real data. One popular solution is to impute missing data so that one complete dataset can be obtained for subsequent data analysis. In the present study, we focus on missing data imputation using classification and regression trees (CART). Methods: We consider a new perspective on missing data in a CART imputation problem and realize the perspective through some resampling algorithms. Several existing missing data imputation methods using CART are compared through simulation studies, and we aim to investigate the methods with better imputation accuracy under various conditions. Some systematic findings are demonstrated and presented. These imputation methods are further applied to two real datasets: Hepatitis data and Credit approval data for illustration. Results: The method that performs the best strongly depends on the correlation between variables. For imputing missing ordinal categorical variables, the rpart package with surrogate variables is recommended under correlations larger than 0 with missing completely at random (MCAR) and missing at random (MAR) conditions. Under missing not at random (MNAR), chi-squared test methods and the rpart package with surrogate variables are suggested. For imputing missing quantitative variables, the iterative imputation method is most recommended under moderate correlation conditions.

CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury.

Ischemic stroke can lead to systemic inflammation, which can activate peripheral immune cells, causing neuroinflammation and brain injury. Meningeal lymphatics play a crucial role in transporting solutes and immune cells out of the brain and draining them into cervical lymph nodes (CLNs). However, the role of meningeal lymphatics in regulating systemic inflammation during the reperfusion stage after ischemia is not well understood. In this study, we demonstrated that brain infarct size, neuronal loss, and the effector function of inflammatory macrophage subsets were reduced after ischemia-reperfusion and disruption of meningeal lymphatics. Spatial memory function was improved in the late stage of ischemic stroke following meningeal lymphatic disruption. Brain-infiltrating immune cells, including neutrophils, monocytes, and T and natural killer cells, were reduced after cerebral ischemia-reperfusion and meningeal lymphatic disruption. Single-cell RNA sequencing analysis revealed that meningeal lymphatic disruption reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN lymphatic endothelial cells (LECs), and it also decreased chemotactic CCN1 expression in floor LECs. Replenishment of CCN1 through intraventricular injection increased brain infarct size and neuronal loss, while restoring numbers of macrophages/microglia in the brains of meningeal lymphatic-disrupted mice after ischemic stroke. Blocking CCN1 in cerebrospinal fluid reduced brain infarcts and improves spatial memory function after ischemia-reperfusion injury. In summary, this study indicates that CCN1-mediated detrimental inflammation was alleviated after cerebral ischemia-reperfusion injury and meningeal lymphatic disruption. CCN1 represents a novel therapeutic target for inhibiting systemic inflammation in the brain-CLN axis after ischemia-reperfusion injury.

Patients Engaged in Losing Weight Preoperatively Experience Improved Outcomes After Hiatal Hernia Repair.

BACKGROUND: Adherence to preoperative weight loss recommendations may serve as a surrogate for the level of engagement in hiatal hernia (HH) patients. This study aims to evaluate the relationship between achieving preoperative weight loss goals and outcomes after HH repair. METHODS: A retrospective review of 235 patients undergoing laparoscopic HH repair at a single institution was performed. Patients were grouped based on the percentage of weight loss goal achieved. Low achievement was defined as the bottom quartile of goal achievement (≤75%); high achievement was defined as the top quartile (≥140%). Baseline characteristics, clinical outcomes, and patient reported outcomes (PROMs) were compared between groups. RESULTS: 131/235 (55.7%) achieved their weight loss goal. No differences in baseline characteristics or clinical outcomes were observed between the low and high achievement groups. While both groups experienced improvements in PROMs postoperatively, patients in the high achievement group demonstrated significantly lower symptom burden at one-month postoperatively. Further, high-achievement patients were more likely to experience complete resolution of common HH symptoms at one-month postoperatively, including no difficulty swallowing food, no breathing difficulties or choking episodes, no choking when eating food, no choking when drinking liquid, and no regurgitation of food or liquid. CONCLUSIONS: In patients undergoing laparoscopic HH repair, patients achieving their preoperative weight loss goals experienced less overall symptom burden and lower prevalence of common symptoms one-month postoperatively than those with low levels of goal achievement. These results demonstrate that patients can take an active role in improving their own surgical outcomes and health status.

Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of combined CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma.

Outcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we performed a phase 0/1 dose-escalation clinical trial that investigated tumor pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics following combined ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) treatment in recurrent high-grade glioma. Patients with a recurrent high-grade glioma (n = 24) harboring 1) CDKN2A / B deletion or CDK4 / 6 amplification, 2) PTEN loss or PIK3CA mutations, and 3) wild-type retinoblastoma protein (Rb) were enrolled. Patients received neoadjuvant ribociclib and everolimus treatment and no dose-limiting toxicities were observed. The median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were 170 nM (range, 65 - 1770 nM) and 634 nM (range, 68 - 2345 nM) in patients receiving 5 days treatment at the daily dose of 400 and 600 mg, respectively. Unbound everolimus concentrations were below the limit of detection (< 0.1 nM) in both enhancing and non-enhancing tumor regions at all dose levels. We identified a significant decrease in MIB1 positive cells suggesting ribociclib-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) based comparisons of 17 IDH-wild-type on-trial recurrences to 31 IDH-wild-type standard of care treated recurrences data demonstrated a significantly lower fraction of cycling and neural progenitor-like (NPC-like) malignant cell populations. We validated the CDK4/6 inhibitor-directed malignant cell state shifts using three patient-derived cell lines. The presented clinical trial highlights the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics to assess treatment effects in phase 0/1 surgical tissues, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740 .

Abnormal p53 expression is associated with poor outcomes in grade I or II, stage I, endometrioid carcinoma: a retrospective single-institute study.

OBJECTIVE: The Cancer Genome Atlas study revealed an association between copy-number high (p53 abnormal) genetic mutation and poor prognosis in endometrial cancer in 2013. This retrospective study investigated outcomes in patients with abnormal p53 expression and stage I, low-grade endometrial endometrioid carcinoma (EEC). METHODS: We enrolled women with stage I, grade 1 or 2 EEC who received comprehensive staging and adjuvant therapy between January 2019 and December 2022 at MacKay Memorial Hospital, Taipei, Taiwan. Pathologists interpreted immunohistochemistry stains of cancerous tissues to detect p53 mutation. We compared recurrence, survival, progression-free survival, and overall survival between p53 abnormal and p53 normal groups. RESULTS: Of the 115 patients included, 26 had pathologically confirmed abnormal p53 expression. Of these 26 patients, five (19.2%) experienced recurrence, and two died due to disease progression. By contrast, no patients in the normal p53 group experienced disease recurrence or died due to disease progression. Significant intergroup differences were discovered in recurrent disease status (19.4% vs. 0%, p<0.001), mortality (7.7% vs. 0%, p<0.001), and progression-free survival (p<0.001). The overall survival (p=0.055) also showed powerful worse trend. CONCLUSION: For patients with stage I, low-grade EEC, abnormal p53 expression may be used as an indicator of poor prognosis. Therefore, we suggest considering aggressive adjuvant therapies for these patients.

Canine Schistosomiasis in the West Coast: Heterobilharzia americana in Two Natural Intermediate Hosts Found in the Colorado River, California.

The emergence of infectious diseases presents a significant global health, economic, and security risk. Climate change can unexpectedly lead to the spread of pathogens, vectors, or hosts into new areas, contributing to the rise of infectious diseases. Surveillance plays a crucial role in monitoring disease trends and implementing control strategies. In this study, we document the first discovery of Heterobilharzia americana, a parasitic schistosome of mammals and its intermediate hosts Galba cubensis and Galba humilis along the banks of the Colorado River in California. We conducted multiple samplings of snails from various locations in the region with a previous history of canine schistosomiasis. Nucleotide sequencing of the multiple regions of the snails' and parasites' DNA revealed the coexistence of G. cubensis and G. humilis, both infected with H. americana. Phylogenetic analyses further validate the presence of H. americana in California, suggesting a wider distribution than previously reported. Our findings have implications for public health, veterinary medicine, and biodiversity conservation, contributing to developing effective control strategies to prevent the spread of this emerging infectious disease.

Identification of bioactive compounds and inhibitory effects of TNF-α and COX-2 in the extract from cultured three-spot seahorse (H. trimaculatus).

Three-spot seahorse (Hippocampus trimaculatus) has been consumed as traditional Chinese medicine in Asian society. This study was designed to analyze the bioactive compounds of the solvent extracts from cultured three-spot seahorse by high pressure liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI/MS/MS). Subsequently, their biological activities were evaluated and confirmed by cell modes and Western blot analysis. Experimental results indicated that taurine and arginine were the primary bioactive compounds identified and quantified without pre- or post-column derivatization within 20 min retention time. The analytical method was established and validated with intraday/interday RSD from 0.25% to 3.34% and with recovery from 87.8% to 91.2%. As compared to other extracts, water layer extract (WLE) contained the most taurine and arginine contents of 6.807 and 0.437 mg/g (dry basis), respectively. In the meanwhile, WLE also showed anti-inflammatory activity on LPS-induced NO production and inhibited the protein expression of TNF-α and COX-2 by Western blot analysis with better cell viability.

Extracellular vesicles incorporating retrovirus-like capsids for the enhanced packaging and systemic delivery of mRNA into neurons.

The blood-brain barrier (BBB) restricts the systemic delivery of messenger RNAs (mRNAs) into diseased neurons. Although leucocyte-derived extracellular vesicles (EVs) can cross the BBB at inflammatory sites, it is difficult to efficiently load long mRNAs into the EVs and to enhance their neuronal uptake. Here we show that the packaging of mRNA into leucocyte-derived EVs and the endocytosis of the EVs by neurons can be enhanced by engineering leucocytes to produce EVs that incorporate retrovirus-like mRNA-packaging capsids. We transfected immortalized and primary bone-marrow-derived leucocytes with DNA or RNA encoding the capsid-forming activity-regulated cytoskeleton-associated (Arc) protein as well as capsid-stabilizing Arc 5'-untranslated-region RNA elements. These engineered EVs inherit endothelial adhesion molecules from donor leukocytes, recruit endogenous enveloping proteins to their surface, cross the BBB, and enter the neurons in neuro-inflammatory sites. Produced from self-derived donor leukocytes, the EVs are immunologically inert, and enhanced the neuronal uptake of the packaged mRNA in a mouse model of low-grade chronic neuro-inflammation.

Connecting genomic results for psychiatric disorders to human brain cell types and regions reveals convergence with functional connectivity.

Understanding the temporal and spatial brain locations etiological for psychiatric disorders is essential for targeted neurobiological research. Integration of genomic insights from genome-wide association studies with single-cell transcriptomics is a powerful approach although past efforts have necessarily relied on mouse atlases. Leveraging a comprehensive atlas of the adult human brain, we prioritized cell types via the enrichment of SNP-heritabilities for brain diseases, disorders, and traits, progressing from individual cell types to brain regions. Our findings highlight specific neuronal clusters significantly enriched for the SNP-heritabilities for schizophrenia, bipolar disorder, and major depressive disorder along with intelligence, education, and neuroticism. Extrapolation of cell-type results to brain regions reveals important patterns for schizophrenia with distinct subregions in the hippocampus and amygdala exhibiting the highest significance. Cerebral cortical regions display similar enrichments despite the known prefrontal dysfunction in those with schizophrenia highlighting the importance of subcortical connectivity. Using functional MRI connectivity from cases with schizophrenia and neurotypical controls, we identified brain networks that distinguished cases from controls that also confirmed involvement of the central and lateral amygdala, hippocampal body, and prefrontal cortex. Our findings underscore the value of single-cell transcriptomics in decoding the polygenicity of psychiatric disorders and offer a promising convergence of genomic, transcriptomic, and brain imaging modalities toward common biological targets.

A bi-criterion sequence-dependent scheduling problem with order deliveries.

The manufacturing sector faces unprecedented challenges, including intense competition, a surge in product varieties, heightened customization demands, and shorter product life cycles. These challenges underscore the critical need to optimize manufacturing systems. Among the most enduring and complex challenges within this domain is production scheduling. In practical scenarios, setup time is whenever a machine transitions from processing one product to another. Job scheduling with setup times or associated costs has garnered significant attention in both manufacturing and service environments, prompting extensive research efforts. While previous studies on customer order scheduling primarily focused on orders or jobs to be processed across multiple machines, they often overlooked the crucial factor of setup time. This study addresses a sequence-dependent bi-criterion scheduling problem, incorporating order delivery considerations. The primary objective is to minimize the linear combination of the makespan and the sum of weighted completion times of each order. To tackle this intricate challenge, we propose pertinent dominance rules and a lower bound, which are integral components of a branch-and-bound methodology employed to obtain an exact solution. Additionally, we introduce a heuristic approach tailored to the problem's unique characteristics, along with three refined variants designed to yield high-quality approximate solutions. Subsequently, these three refined approaches serve as seeds to generate three distinct populations or chromosomes, each independently employed in a genetic algorithm to yield a robust approximate solution. Ultimately, we meticulously assess the efficacy of each proposed algorithm through comprehensive simulation trials.

Acrylamide, an air pollutant, enhances allergen-induced eosinophilic lung inflammation via group 2 innate lymphoid cells.

Air pollution significantly impacts the aggravation of asthma. Exposure to acrylamide, a volatile organic compound in tobacco smoke, is associated with elevated risks of allergy-related outcomes among active smokers. As group 2 innate lymphoid cells (ILC2s) can act as an environmental sensor and significantly contribute to protease allergen-induced lung inflammation, we aimed to elucidate the causal relationship and how inhaled acrylamide worsens allergic lung inflammation via ILC2s. Intranasal acrylamide exposure at nanomolar levels significantly enhanced allergen-induced or recombinant mouse interleukin-33-induced lung inflammation in C57BL/6 mice or Rag1-/- mice, respectively. The cardinal features of lung inflammation included accumulated infiltration of ILC2s and eosinophils. Transcriptomic analysis revealed a gene expression pattern associated with proliferation-related pathways in acrylamide-treated ILC2s. Western blotting revealed significantly higher expression of Ras and phospho-Erk in acrylamide-treated ILC2s than the control, suggesting Ras-Erk signaling pathway involvement. Ex vivo and in vitro analysis showed that acrylamide treatment mainly increased Ki-67+ ILC2s and the cell number of ILC2s whereas PD98059, a highly selective Erk inhibitor, effectively counteracted the acrylamide effect. Intratracheal administration of acrylamide-treated ILC2s significantly enhanced eosinophil infiltration in Rag1-/- mice. This study suggests that airborne acrylamide may enhance the severity of allergen-induced airway eosinophilic inflammation, partly via altering ILC2 proliferative activity.

Unscarred uterine rupture with catastrophic hemorrhage immediately after vaginal delivery: diagnosis and management of six consecutive cases.

BACKGROUND: To describe and explore the risk factors, clinical presentations, timely diagnostic approaches, and management in patients experiencing unscarred uterine rupture with catastrophic hemorrhage. METHODS: We retrospectively analyzed clinical and imaging data from women who encountered postpartum hemorrhage (PPH) and were diagnosed with unscarred uterine rupture within a three-year timeframe (2018-2020). The data were extracted from medical records obtained from a multi-hospital 24-hour emergency PPH transfer system. RESULTS: Six patients were identified as having unscarred uterine rupture after vaginal delivery. All six women were para 2, with four of them undergoing vacuum-assisted delivery. One patient experienced out-of-hospital cardiac arrest (OHCA), while five patients presented with hypovolemic shock. Abdominopelvic ultrasound revealed a boggy lower uterine segment. Initially, five patients underwent transarterial embolization (TAE) of the internal iliac arteries in an attempt to achieve hemostasis, but this approach proved unsuccessful. Abdominopelvic computed tomography (CT) confirmed the diagnosis of ruptured uterus by demonstrating disrupted myometrium and hemoperitoneum. Immediate exploratory laparotomy followed by life-saving hysterectomy was performed in all cases. The median estimated total blood loss was 2725 mL ± 900 mL (ranging from 1600 mL to 7100 mL). Lower segment lacerations were observed in all patients, with more extensive uterine damage noted in those who underwent vacuum extraction. The length of hospital stay varied between 9 and 38 days. CONCLUSION: Instrument-assisted obstetric delivery is a possible contributing factor to unscarred uterine rupture in our study. In specific cases, the use of abdominopelvic CT prior to initiating transarterial embolization (TAE) offers valuable information to complement ultrasound findings. This comprehensive approach helps in accurately identifying the underlying cause of intractable postpartum hemorrhage (PPH). Immediate conversion to laparotomy is essential to explore the intra-abdominal factors causing PPH that cannot be controlled by TAE. The rational etiologies of uterine rupture must be clarified while generating practical guideline in the future.

Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions.

The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging, and whether it is associated with cognition and mood. Here, we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years of age (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project [HCP] 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory, and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography, and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale (HADS) ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology.

Characterization of pathogenic factors for premenstrual dysphoric disorder using machine learning algorithms in rats.

We established a methodology using machine learning algorithms for determining the pathogenic factors for premenstrual dysphoric disorder (PMDD). PMDD is a disease characterized by emotional and physical symptoms that occurs before menstruation in women of childbearing age. Owing to the diverse manifestations and various pathogenic factors associated with this disease, the diagnosis of PMDD is time-consuming and challenging. In the present study, we aimed to establish a methodology for diagnosing PMDD. Using an unsupervised machine-learning algorithm, we divided pseudopregnant rats into three clusters (C1 to C3), depending on the level of anxiety- and depression-like behaviors. From the results of RNA-seq and subsequent qPCR of the hippocampus in each cluster, we identified 17 key genes for building a PMDD diagnostic model using our original two-step feature selection with supervised machine learning. By inputting the expression levels of these 17 genes into the machine learning classifier, the PMDD symptoms of another group of rats were successfully classified as C1-C3 with an accuracy of 96%, corresponding to the classification by behavior. The present methodology would be applicable for the clinical diagnosis of PMDD using blood samples instead of samples from the hippocampus in the future.