Role of aldosterone in various target organ damage in patients with hypertensive emergency: a cross-sectional study.

BACKGROUND: Hypertensive emergency is a critical disease that causes multiple organ injuries. Although the renin-angiotensin-aldosterone system (RAS) is enormously activated in this disorder, whether the RAS contributes to the development of the organ damage has not been fully elucidated. This cross-sectional study was conducted to characterize the association between RAS and the organ damage in patients with hypertensive emergencies. METHODS: We enrolled 63 patients who visited our medical center with acute severe hypertension and multiple organ damage between 2012 and 2020. Hypertensive target organ damage was evaluated on admission, including severe kidney impairment (eGFR less than 30 mL/min/1.73 m2, SKI), severe retinopathy, concentric left ventricular hypertrophy (c-LVH), thrombotic microangiopathy (TMA), heart failure with reduced ejection fraction (HFrEF) and cerebrovascular disease. Then, whether each organ injury was associated with blood pressure or a plasma aldosterone concentration was analyzed. RESULTS: Among 63 patients, 31, 37, 43 and 8 cases manifested SKI, severe retinopathy, c-LVH and ischemic stroke, respectively. All populations with the organ injuries except cerebral infarction had higher plasma aldosterone concentrations than the remaining subset but exhibited a variable difference in systolic or diastolic blood pressure. Twenty-two patients had a triad of SKI, severe retinopathy and c-LVH, among whom 5 patients manifested TMA. Furthermore, the number of the damaged organs was correlated with plasma aldosterone levels (Spearman's coefficient = 0.50), with a strong association observed between plasma aldosterone (≥ 250 pg/mL) and 3 or more complications (odds ratio = 9.16 [95%CI: 2.76-30.35]). CONCLUSION: In patients with hypertensive emergencies, a higher aldosterone level not only contributed to the development of the organ damage but also was associated with the number of damaged organs in each patient.

Safety and tolerability of a Muse cell-based product in neonatal hypoxic-ischemic encephalopathy with therapeutic hypothermia (SHIELD trial).

Hypoxic-ischemic encephalopathy (HIE), associated with high mortality and neurological sequelae, lacks established treatment except therapeutic hypothermia. Clinical-grade multilineage-differentiating stress-enduring (Muse) cells (CL2020) demonstrated safety and efficacy in nonclinical HIE rat models, thereby leading to an investigator-initiated clinical trial to evaluate CL2020 safety and tolerability in neonatal HIE as a single-center open-label dose-escalation study with 9 neonates with moderate-to-severe HIE who received therapeutic hypothermia. Each patient received a single intravenous injection of CL2020 cells between 5 and 14 days of age. The low-dose (3 patients) and high-dose (6 patients) groups received 1.5 × 106 and 1.5 × 107 cells/dose, respectively. The occurrence of any adverse event within 12 weeks following CL2020 administration was the primary endpoint of this trial. No significant changes in physiological signs including heart rate, blood pressure, and oxygen saturation were observed during or after administration. The only adverse event that may be related to cell administration was a mild γ-glutamyltransferase level elevation in one neonate, which spontaneously resolved without any treatment. All patients enrolled in the trial survived, and normal developmental quotients (≥ 85) in all 3 domains of the Kyoto Scale of Psychological Development 2001 were observed in 67% of the patients in this trial. CL2020 administration was demonstrated to be safe and tolerable for neonates with HIE. Considering the small number of patients, a randomized controlled confirmatory study is warranted to verify these preliminary findings and evaluate the efficacy of this therapy.

Caspase-11 mediated inflammasome activation in macrophages by systemic infection of A. actinomycetemcomitans exacerbates arthritis.

Clinical studies have shown that Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is associated with aggressive periodontitis and can potentially trigger or exacerbate rheumatoid arthritis (RA). However, the mechanism is poorly understood. Here, we show that systemic infection with A. actinomycetemcomitans triggers the progression of arthritis in mice anti-collagen antibody-induced arthritis (CAIA) model following IL-1ß secretion and cell infiltration in paws in a manner that is dependent on caspase-11-mediated inflammasome activation in macrophages. The administration of polymyxin B (PMB), chloroquine, and anti-CD11b antibody suppressed inflammasome activation in macrophages and arthritis in mice, suggesting that the recognition of lipopolysaccharide (LPS) in the cytosol after bacterial degradation by lysosomes and invasion via CD11b are needed to trigger arthritis following inflammasome activation in macrophages. These data reveal that the inhibition of caspase-11-mediated inflammasome activation potentiates aggravation of RA induced by infection with A. actinomycetemcomitans. This work highlights how RA can be progressed by inflammasome activation as a result of periodontitis-associated bacterial infection and discusses the mechanism of inflammasome activation in response to infection with A. actinomycetemcomitans.

Colistin Resistance Mediated by Mcr-3-Related Phosphoethanolamine Transferase Genes in Aeromonas Species Isolated from Aquatic Environments in Avaga and Pakro Communities in the Eastern Region of Ghana.

Purpose: Colistin is classified by the World Health Organization (WHO) as a critically important and last-resort antibiotic for the treatment of infections caused by carbapenem-resistant bacteria. However, colistin resistance mediated by chromosomal mutations or plasmid-linked mobilized colistin resistance (mcr) genes has emerged. Methods: Thirteen mcr-positive Aeromonas species isolated from water samples collected in Eastern Ghana were analyzed using whole-genome sequencing (WGS). Antimicrobial susceptibility was tested using the broth microdilution method. Resistome analysis was performed in silico using a web-based platform. Results: The minimum inhibitory concentration (MIC) of colistin for all except three isolates was >4 µg/mL. Nine new sequence types were identified and whole-genome analysis revealed that the isolates harbored genes (mcr-3-related genes) that code for Lipid A phosphoethanolamine transferases on their chromosomes. BLAST analysis indicated that the amino acid sequences of the mcr-3-related genes detected varied from those previously reported and shared 79.04-99.86% nucleotide sequence identity with publicly available mcr-3 variants and mcr-3-related phosphoethanolamine transferases. Analysis of the genetic context of mcr-3-related genes revealed that the genetic environment surrounding mcr-3-related genes was diverse among the different species of Aeromonas but conserved among isolates of the same species. Mcr-3-related-gene-IS-mcr-3-related-gene segment was identified in three Aeromonas caviae strains. Conclusion: The presence of mcr-3-related genes close to insertion elements is important for continuous monitoring to better understand how to control the mobilization and dissemination of antibiotic resistance genes.

A Case of Thrombocytopenia, Anasarca (Edema, Pleural Effusion, and Ascites), Fever, Reticulin Fibrosis/Renal Dysfunction, and Organomegaly (TAFRO) Syndrome Initially Not Presenting With Thrombocytopenia: A Role of Immature Platelet Fraction.

Thrombocytopenia, anasarca (edema, pleural effusion, and ascites), fever, reticulin fibrosis/renal dysfunction, and organomegaly (TAFRO) syndrome is a rare and severe systemic disease. The emergence of thrombocytopenia, however, may be preceded by other signs or symptoms, which could delay the diagnosis of the disease. We reported a case in which an increased immature platelet fraction (IPF), a surrogate marker for megakaryocytic activity, preceded the development of thrombocytopenia, and finally, we diagnosed the patient with TAFRO syndrome. A 79-year-old male with a previous history of uninephrectomy due to bladder and ureteral cancer was admitted to our hospital because of massive edema and progressive impairment in renal function. On admission, inguinal lymphadenopathy, elevated C-reactive protein (CRP), bilateral pleural effusion, and ascites were observed, and the lymph node biopsy showed that atrophic lymphoid follicles and germinal centers were observed along with prominent glomeruloid vascular proliferation and the expansion of the interfollicular spaces consistent with the feature of Castleman's disease. The peripheral platelet count did not reach the level of the criteria for TAFRO syndrome (13.9×104/µL), but the immature platelet fraction was increased (11.6%), and bone marrow biopsy revealed hyperplasia of megakaryocytes. During the course of the preemptive treatment with prednisolone and tocilizumab, thrombocytopenia was uncovered, and the patient was finally diagnosed as having TAFRO syndrome. Thus, the present case may offer valuable information on the role of the immature platelet fraction in the establishment of the early diagnosis of TAFRO syndrome.

Comparative evaluation of analytical pipelines for illumina short- and nanopore long-read 16S rRNA gene amplicon sequencing with mock microbial communities.

Utility of a recently developed long-read pipeline, Emu, was assessed using an expectation-maximization algorithm for accurate read classification. We compared it to conventional short- and long-read pipelines, using well-characterized mock bacterial samples. Our findings highlight the necessity of appropriate data-processing for taxonomic descriptions, expanding our understanding of the precise microbiome.

TAK1-binding protein 2 (TAB2) and TAB3 are redundantly required for TLR-induced cytokine production in macrophages.

Transforming growth factor-ß-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to the lysine 63-linked polyubiquitin chain through TAK1-binding protein 2 (TAB2) and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and TAB3 are dispensable for TLR signaling. In this study, we revisited the role of TAB2 and TAB3 using an improved mouse model. We observed a significant impairment in the production of pro-inflammatory cytokines and chemokine in LPS- or Pam3CSK4-treated BMDMs deficient for both TAB2 and TAB3. Double deficiency of TAB2 and TAB3 resulted in the decreased activation of NF-κB and MAPK pathways as well as the slight decrease in TAK1 activation in response to LPS or Pam3CSK4. Notably, the TLR-mediated expression of inhibitor of NF-κB (IκB)ζ was severely compromised at the protein and messenger RNA (mRNA) levels in the TAB2/TAB3 double-deficient BMDMs, thereby impeding IL-6 production. Our results suggest that TAB2 and TAB3 play a redundant and indispensable role in the TLR signaling pathway.

Total Hydrocortisone Dosage in the Neonatal Period May Be Related to Low Developmental Quotient in Extremely Low Birth Weight Infants: A Retrospective Cohort Study.

INTRODUCTION: The effects of hydrocortisone (HDC) administration to extremely low birth weight (ELBW) infants on later development remain unclear. This study examined the association between HDC dosage during neonatal period and neurodevelopmental outcomes in ELBW infants. METHODS: This study was a retrospective cohort study conducted in eight centers in Japan. The subjects of this study were ELBW infants born between April 2015 and March 2017. The association between postnatal total HDC dosage up to 36 weeks postmenstrual age and the developmental quotient (DQ) at 3 years of age was examined. Multiple linear regression evaluated the association, adjusting for weeks of gestation, birth weight, and the presence of bronchopulmonary dysplasia, late-onset circulatory collapse, intracranial hemorrhage, necrotizing enterocolitis, and sepsis. RESULTS: This study included 218 ELBW infants, of whom 144 underwent a developmental test at 3 years of age. Simple linear regression analysis revealed a significant association between total HDC dosage and DQ at 3 years of age (coefficients: -2.65, 95% CI: -3.73, -1.57). Multiple linear regression analysis adjusted for the presence of bronchopulmonary dysplasia and late-onset circulatory collapse also revealed a significant association between total HDC dosage and DQ at 3 years of age (coefficients: -2.66, 95% CI: -3.89, -1.42). CONCLUSION: Higher total HDC dosage up to 36 weeks postmenstrual age in ELBW infants was associated with impaired neurodevelopmental outcomes. Although HDC is often needed in the treatment of ELBW infants, clinicians should be aware that an increased dose of HDC may be associated with impaired neurodevelopmental outcomes.

A case report of forensic personal identification by transposed teeth and dental treatment marks using multidetector row computed tomography.

Using postmortem computed tomography (CT) images, we achieved personal identification of a body using transposed teeth and dental treatment marks. Transposition of teeth is a rare malpositioning anomaly. CT images can clarify the malpositioning of the teeth's roots, which is difficult to discern from gross observation of the dentition. Because dental hygiene has reduced the incidence of caries in recent years, it might be difficult to use treatment marks for personal identification in the future. Transposed teeth, although rare, provide an important clue to personal identification.

[Early Structural Valve Deterioration of Trifecta Aortic Bioprosthesis:Report of a Case].

Trifecta, an externally mounted bovine pericardial bioprosthetic aortic valve, provides excellent hemodynamic performance;however, early structural deterioration of this valve has been reported. A 60-year-old man with progressive dyspnea was admitted to the emergency unit of our institution. Seven years prior, he underwent aortic valve replacement with 23-mm Trifecta valve. Severe aortic valve regurgitation and stenosis due to structural valve deterioration was diagnosed and redo aortic valve replacement using an Inspiris valve was performed. Intraoperative findings revealed a large laceration in the left coronary cusp adjacent to the non coronary-left coronary commissure and leaflet calcification. Further, circumferential fibrous pannus ingrowth at the inflow portion was also noted. To avoid anticoagulation therapy and repeat surgery, mitral valve plasty and left atrial appendage clipping were performed simultaneously. Postoperative course was uneventful, and he was transferred to a rehabilitation facility on 36th postoperative day.

Emergence of Intergenogroup Reassortant G9P[4] Strains Following Rotavirus Vaccine Introduction in Ghana.

Rotavirus (RVA) is a leading cause of childhood gastroenteritis. RVA vaccines have reduced the global disease burden; however, the emergence of intergenogroup reassortant strains is a growing concern. During surveillance in Ghana, we observed the emergence of G9P[4] RVA strains in the fourth year after RVA vaccine introduction. To investigate whether Ghanaian G9P[4] strains also exhibited the DS-1-like backbone, as seen in reassortant G1/G3/G8/G9 strains found in other countries in recent years, this study determined the whole genome sequences of fifteen G9P[4] and two G2P[4] RVA strains detected during 2015-2016. The results reveal that the Ghanaian G9P[4] strains exhibited a double-reassortant genotype, with G9-VP7 and E6-NSP4 genes on a DS-1-like backbone (G9-P[4]-I2-R2-C2-M2-A2-N2-T2-E6-H2). Although they shared a common ancestor with G9P[4] DS-1-like strains from other countries, further intra-reassortment events were observed among the original G9P[4] and co-circulating strains in Ghana. In the post-vaccine era, there were significant changes in the distribution of RVA genotype constellations, with unique strains emerging, indicating an impact beyond natural cyclical fluctuations. However, reassortant strains may exhibit instability and have a limited duration of appearance. Current vaccines have shown efficacy against DS-1-like strains; however, ongoing surveillance in fully vaccinated children is crucial for addressing concerns about long-term effectiveness.

Inflammasome-triggered IL-18 controls skin inflammation in the progression of Buruli ulcer.

Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence factor so far, but the functions of this toxin and the mechanisms of disease progression remain unclear. By interfering Sec61 translocon, mycolactone inhibits the Sec61-dependent co-translational translocation of newly synthesized proteins, such as induced cytokines and immune cell receptors, into the endoplasmic reticulum. However, in regard to IL-1ß, which is secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1ß secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1ß, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the inflammasome activation triggered in a manner independent of mycolactone. Intriguingly, mycolactone suppressed the expression of proIL-1ß as well as TNF-α at the transcriptional level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional inhibitory effect on proIL-1ß expression. Remarkably, constitutively produced IL-18 was cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans exhibited exacerbated skin inflammation during the course of disease progression. On the other hand, IL-1ß controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of Buruli ulcer.

Validation study of EuroSCORE II for dialysis patients: A single-center study in Japan.

BACKGROUND: The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II is a predictive model for in-hospital mortality after cardiac surgery. Although it has good performance among the general population undergoing cardiac surgery, it has not been validated among dialysis patients, who have a higher rate of mortality after cardiac surgery. This study aimed to evaluate the performance of the model in predicting in-hospital mortality in maintenance dialysis patients undergoing cardiac surgery. METHODS: This retrospective, single-center study included adult patients on maintenance dialysis who underwent open cardiac surgery at our institution. Calibration performance of EuroSCORE II for in-hospital death was determined based on the comparison between expected and observed mortalities for low- (EuroSCORE II <4 %), intermediate- (4-8 %), and high-risk (>8 %) groups. The area under receiver operating characteristic curve (AUROC) was investigated to determine the model's discrimination performance. RESULTS: A total of 163 patients (male, 73.6 %; median age, 70 years; median dialysis vintage, 9 years; median EuroSCORE II, 3.3 %) were included. The mortality rate was 9.2 %. The observed mortality rates (vs. mean expected mortality) rates were 2.1 % (vs. 2.4 %), 7.5 % (vs. 5.5 %), and 34.5 % (vs. 21.1 %) in the low-, intermediate-, and high-risk groups, respectively. Its AUROC was 0.825 (95 % confidence interval, 0.711-0.940). CONCLUSIONS: Although EuroSCORE II model adequately estimated in-hospital mortality in the low-and intermediate-risk groups (EuroSCORE II <8 %), it underestimated in-hospital mortality in the high-risk group (EuroSCORE II >8 %) among maintenance dialysis patients. The discrimination performance of the model for in-hospital death was good among maintenance dialysis patients.

Systemic administration of clinical-grade multilineage-differentiating stress-enduring cells ameliorates hypoxic-ischemic brain injury in neonatal rats.

Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ connective tissues. We assessed the homing and therapeutic effects of systemically administered nafimestrocel, a clinical-grade human Muse cell-based product, without immunosuppressants in a neonatal hypoxic-ischemic (HI) rat model. HI injury was induced on postnatal day 7 (P7) and was confirmed by T2-weighted magnetic resonance imaging on P10. HI rats received a single dose nafimestrocel (1 × 106 cells/body) or Hank's balanced salt solution (vehicle group) intravenously at either three days (on P10; M3 group) or seven days (on P14; M7 group) after HI insult. Radioisotope experiment demonstrated the homing of chromium-51-labeled nafimestrocel to the both cerebral hemispheres. The cylinder test (M3 and M7 groups) and open-field test (M7 group) showed significant amelioration of paralysis and hyperactivity at five weeks of age compared with those in the vehicle group. Nafimestrocel did not cause adverse events such as death or pathological changes in the lung at ten weeks in the both groups. Nafimestrocel attenuated the production of tumor necrosis factor-α and inducible nitric oxide synthase from activated cultured microglia in vitro. These results demonstrate the potential therapeutic benefits and safety of nafimestrocel.

Estimation of external dose for wild Japanese macaques captured in Fukushima prefecture: decomposition of electron spin resonance spectrum.

The signal intensities of CO2- radicals in teeth can be utilised as an individual indicator of the cumulative external dose for animals. To accurately determine the external dose, it is desirable to analyse the CO2- radical intensity and improve its detection limit. We recently reported a dose-response in the range of 0-200 mGy and estimated the absorbed dose for seven wild Japanese macaques captured in/around the related areas to the Fukushima Daiichi Nuclear Power Plant accident. Herein, for further improvement of this method, we examined the electron spin resonance spectra of the teeth of these seven and an additional four macaques captured in Fukushima by applying two spectrum-decomposition algorithms.

The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis.

The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

D-amino Acids Ameliorate Experimental Colitis and Cholangitis by Inhibiting Growth of Proteobacteria: Potential Therapeutic Role in Inflammatory Bowel Disease.

BACKGROUND & AIMS: D-amino acids, the chiral counterparts of protein L-amino acids, were primarily produced and utilized by microbes, including those in the human gut. However, little was known about how orally administered or microbe-derived D-amino acids affected the gut microbial community or gut disease progression. METHODS: The ratio of D- to L-amino acids was analyzed in feces and blood from patients with ulcerative colitis (UC) and healthy controls. Also, composition of microbe was analyzed from patients with UC. Mice were treated with D-amino acid in dextran sulfate sodium colitis model and liver cholangitis model. RESULTS: The ratio of D- to L-amino acids was lower in the feces of patients with UC than that of healthy controls. Supplementation of D-amino acids ameliorated UC-related experimental colitis and liver cholangitis by inhibiting growth of Proteobacteria. Addition of D-alanine, a major building block for bacterial cell wall formation, to culture medium inhibited expression of the ftsZ gene required for cell fission in the Proteobacteria Escherichia coli and Klebsiella pneumoniae, thereby inhibiting growth. Overexpression of ftsZ restored growth of E. coli even when D-alanine was present. We found that D-alanine not only inhibited invasion of pathological K. pneumoniae into the host via pore formation in intestinal epithelial cells but also inhibited growth of E. coli and generation of antibiotic-resistant strains. CONCLUSIONS: D-amino acids might have potential for use in novel therapeutic approaches targeting Proteobacteria-associated dysbiosis and antibiotic-resistant bacterial diseases by means of their effects on the intestinal microbiota community.

Altered offspring neurodevelopment in an L-NAME-induced preeclampsia rat model.

Introduction: To investigate the mechanism underlying the increased risk of subsequent neurodevelopmental disorders in children born to mothers with preeclampsia, we evaluated the neurodevelopment of offspring of a preeclampsia rat model induced by the administration of N-nitro-L-arginine methyl ester (L-NAME) and identified unique protein signatures in the offspring cerebrospinal fluid. Methods: Pregnant rats received an intraperitoneal injection of L-NAME (250 mg/kg/day) during gestational days 15-20 to establish a preeclampsia model. Behavioral experiments (negative geotaxis, open-field, rotarod treadmill, and active avoidance tests), immunohistochemistry [anti-neuronal nuclei (NeuN) staining in the hippocampal dentate gyrus and cerebral cortex on postnatal day 70], and proteome analysis of the cerebrospinal fluid on postnatal day 5 were performed on male offspring. Results: Offspring of the preeclampsia dam exhibited increased growth restriction at birth (52.5%), but showed postnatal catch-up growth on postnatal day 14. Several behavioral abnormalities including motor development and vestibular function (negative geotaxis test: p < 0.01) in the neonatal period; motor coordination and learning skills (rotarod treadmill test: p = 0.01); and memory skills (active avoidance test: p < 0.01) in the juvenile period were observed. NeuN-positive cells in preeclampsia rats were significantly reduced in both the hippocampal dentate gyrus and cerebral cortex (p < 0.01, p < 0.01, respectively). Among the 1270 proteins in the cerebrospinal fluid identified using liquid chromatography-tandem mass spectrometry, 32 were differentially expressed. Principal component analysis showed that most cerebrospinal fluid samples achieved clear separation between preeclampsia and control rats. Pathway analysis revealed that differentially expressed proteins were associated with endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins, which are involved in various nervous system disorders including autism spectrum disorders, schizophrenia, and Alzheimer's disease. Conclusion: The offspring of the L-NAME-induced preeclampsia model rats exhibited key features of neurodevelopmental abnormalities on behavioral and pathological examinations similar to humans. We found altered cerebrospinal fluid protein profiling in this preeclampsia rat, and the unique protein signatures related to endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins may be associated with subsequent adverse neurodevelopment in the offspring.