Elevated arginine vasopressin levels surrogate acute lung injury in acute decompensated heart failure.

Activated arginine vasopressin (AVP) pathway worsens congestion in heart failure (HF), but its potential to relieve pulmonary congestion is also reported. The pathophysiological role and prognostic utility of AVP elevation in acute decompensated HF (ADHF) are poorly understood. We prospectively enrolled 52 hospitalized patients for ADHF to investigate the association between acute lung injury (ALI) in ADHF and AVP levels on admission. ALI was defined as respiratory failure leading to death, or requiring a respirator or a more than 12-h non-invasive intermittent positive pressure ventilation (NIPPV) support. In addition, we investigated the prognostic value of AVP levels on admission for cardiovascular death or recurrence of ADHF after discharge. ALI was documented in 7 patients (13.5%) during a median hospital stay of 14 days. And the patients with ALI demonstrated significantly higher AVP levels than those without (32.5 ± 21.6 vs. 6.4 ± 8.7 pg/ml, p = 0.018). Besides, the patients with ALI demonstrated significantly higher heart rates (HR) and lower E/e' on admission (HR: 127 ± 24 vs. 97 ± 28 bpm; E/e': 10.6 ± 3.7 vs. 17.4 ± 6.2, all p < 0.05, respectively). Of note, significant hemodilution assessed by hemoglobin and hematocrit values were observed in the patients with ALI 48 h after admission. A receiver operating characteristic curve analysis showed that higher than 7.2 pg/ml surrogate ALI in ADHF (AUC: 0.897, p = 0.001, Sensitivity: 85.7%, and Specificity: 77.8%). In contrast, increased AVP levels on admission could not predict cardiovascular events after discharge. Elevated AVP levels on admission are associated with ALI in ADHF but not cardiovascular events after discharge.

Association Between Aortic Stiffness and Exercise Tolerance in Patients at the Risk Stage of Heart Failure.

BACKGROUND: The number of patients with heart failure (HF) has increased, and it is crucial to prevent the development of HF in patients at risk of HF. The present study aimed to risk stratify patients in Stage A and B HF based on associations between exercise-induced changes in aortic stiffness and exercise tolerance.Methods and Results: Patients in Stage A and B HF who performed a cardiopulmonary exercise test were enrolled in the study (n=106; median age 65.0 years [interquartile range 52.8-73.0 years]). Exercise tolerance was examined by the percentage of predicted peak oxygen consumption (%V̇O2peak). The ascending aortic pressure waveform was estimated non-invasively. Aortic stiffness was assessed using the augmentation index (AIx) and reflection magnitude (RM). Multivariable regression analysis showed that AIx measured both before and after exercise was significantly associated with %V̇O2peak (ß=-0.221 [P=0.049] and ß=-0.342 [P=0.003], respectively). When participants were divided into %V̇O2peak subgroups using a cut-off value of 60%, RM decreased immediately after exercise and remained lower 5 min after exercise in the group with preserved exercise tolerance, but recovered to baseline levels 5 min after exercise in the group with reduced exercise tolerance. CONCLUSIONS: Exercise-induced increases in aortic stiffness were associated with exercise tolerance in patients at risk of HF, suggesting that exercise-induced changes in aortic stiffness may be useful to stratify high-risk patients.

Ectopic pancreatic acinar cell carcinoma in the thoracic cavity of F344 rat.

Ectopic pancreatic tissue can occasionally cause inflammation, hemorrhage, stenosis, and invagination, similar to normal pancreatic tissue; however, tumorigenesis is rare. This case report describes an ectopically observed pancreatic acinar cell carcinoma in the thoracic cavity of a female Fischer (F344/DuCrlCrlj) rat. Histopathologically, polygonal tumor cells with periodic acid-Schiff-positive cytoplasmic eosinophilic granules showed solid proliferation and infrequently formed acinus-like structures. Immunohistochemically, the tumor cells were positive for cytokeratin, trypsin, and human B-cell leukemia/lymphoma 10, which specifically reacted with pancreatic acinar cells, and negative for vimentin and human α-smooth muscle actin. Ectopic pancreas develops in the submucosa of the gastrointestinal tract; however, there are few reports of its development and neoplasia in the thoracic cavity. To the best of our knowledge, this is the first report of ectopic pancreatic acinar cell carcinoma in the thoracic cavity of a rat.

Smooth muscle hamartoma of the lungs in a Wistar Hannover rat.

Hamartomas are tumor-like masses comprising disorganized normal tissue elements. To date, spontaneous hamartomas have been reported in several organs and tissues in rodents but not in the lungs. Here, we report the first case of a hamartoma in the lungs of a 108-week-old female Wistar Hannover rat. Grossly, a white spot, 7 mm in diameter, was observed on the costal surface of the left lung. Histopathologically, the nodular lesions adjacent to the bronchioles comprised mature smooth muscle cells. The lesion was not encapsulated and spread along the alveolar walls and ducts without compression of the surrounding tissue. In the nodules, elastic fibers enclosed small lumens lined with factor VIII-related antigen-positive endothelial cells. This structure suggested that the nodule mimicked an artery. Moreover, structural abnormalities were observed within the bronchioles and arterioles owing to the increased number of smooth muscle cells in the surrounding tissues. These features suggested that this was a case of tissue malformation rather than a neoplasm, leading to the diagnosis of a smooth muscle hamartoma of the lung.

[An Intraductal Papillary Mucinous Neoplasm of the Pancreas with Metachronous Quadruple Cancers].

The patient described herein was diagnosed with left breast, endometrial, and early gastric cancers at 49, 53, and 57 years of age, respectively. Magnetic resonance cholangiopancreatography performed when she was undergoing treatment for cholecystitis at 50 years of age showed local pancreatic duct dilatation in the pancreatic head. She was followed in the Department of Gastroenterology at our hospital for an intraductal papillary mucinous neoplasm(IPMN). An abdominal computed tomography scan obtained at 59 years of age revealed dilation of the main pancreatic duct in the pancreas body and tail, therefore an endoscopic ultrasound-guided fine needle aspiration was performed. She was diagnosed with pancreatic cancer and underwent a laparoscopic distal pancreatectomy. The postoperative course was uneventful; however, the pancreatic cancer recurred and she died approximately 14 months postoperatively. Reports of multiple cancers associated with IPMNs are rare, yet we managed a patient with a pancreatic head IPMN complicated by metachronous quadruple carcinomas( breast, endometrial, gastric, and pancreatic cancers).

TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan.

PURPOSE: The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program. METHODS: TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs). RESULTS: A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts. CONCLUSIONS: We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

Impact of malondialdehyde-modified low-density lipoprotein on clinical outcomes after fractional flow reserve-guided deferral of revascularization.

Cardiovascular events can occur after deferred revascularization, and malondialdehyde-modified low-density lipoprotein (MDA-LDL) has been suggested to be an atherogenic marker. We investigated the relationship between serum MDA-LDL levels and clinical outcomes in patients with fractional flow reserve (FFR)-guided deferral of revascularization. Among 3084 patients undergoing coronary angiography, we retrospectively analyzed 127 patients with intermediate stenosis and deferred revascularization based on FFR > 0.80. Median follow-up interval was 30.4 months, and serum MDA-LDL was measured prior to the measurement of FFR. We evaluated the composite of major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, ischemia-driven deferred lesion revascularization, and any revascularization. MACEs occurred in 18 (14.2%) patients. The MACE group presented with significantly higher MDA-LDL levels than the non-MACE group (134.9 ± 33.3 U/L vs. 95.6 ± 32.2 U/L, P < 0.001). In analysis of the receiver operating characteristics curve for the prediction of MACEs, MDA-LDL presented a significantly larger area under the curve than low-density lipoprotein-cholesterol (LDL-C; 0.810 vs. 0.687, P = 0.042). Univariate Cox regression analysis indicated a significant relationship between MACEs and MDA-LDL (per 10 U/L, HR 1.20; P = 0.004), as did the multivariate model (per 10 U/L, HR 1.17; P = 0.019). When compared according to the median LDL-C (98 mg/dL), the MACE group had significantly higher MDA-LDL in both the high (147.2 ± 27.3 U/L vs. 113.9 ± 31.2 U/L, P = 0.001) and low (103.2 ± 27.3 U/L vs. 80.2 ± 24.0 U/L, P = 0.045) LDL-C groups. Serum MDA-LDL levels were associated with cardiac events in patients with deferral of revascularization based on FFR.

Stomach and colonic microbiome of wild Japanese macaques.

Within the gastrointestinal tract, the physiochemical microenvironments are highly diversified among the different stages of food digestion. Accordingly, gut microbiome composition and function vary at different gut sites. In this study, we examine and compare the compositional and functional potential between the stomach and colonic microbiome of wild Japanese macaques (Macaca fuscata yakui) living in the evergreen forest of Yakushima Island. We find a significantly lower microbial diversity in the stomach than in the colon, possibly due to the stomach's acidic and aerobic environment, which is suboptimal for microbial survival. According to past studies, the microbial taxa enriched in the stomach are aero- and acid-tolerant. By functional prediction through PICRUSt2, we reveal that the stomach microbiome is more enriched in pathways relating to the metabolism of simple sugars. On the contrary, the colonic microbiota is more enriched with fiber-degrading microbes, such as those from Lachnospiracea, Ruminococcaceae, and Prevotella. Our study shows a clear difference in the microbiome between the stomach and colon of Japanese macaques in both composition and function. This study provides a preliminary look at the alpha diversity and taxonomic composition within the stomach microbiome of Japanese macaques, a hindgut-fermenting nonhuman primate.

Secondary contact and genomic admixture between rhesus and long-tailed macaques in the Indochina Peninsula.

Understanding the process and consequences of hybridization is one of the major challenges in evolutionary biology. A growing body of literature has reported evidence of ancient hybridization events or natural hybrid zones in primates, including humans; however, we still have relatively limited knowledge about the pattern and history of admixture because there have been little studies that simultaneously achieved genome-scale analysis and a geographically wide sampling of wild populations. Our study applied double-digest restriction site-associated DNA sequencing to samples from the six localities in and around the provisional hybrid zone of rhesus and long-tailed macaques and evaluated population structure, phylogenetic relationships, demographic history, and geographic clines of morphology and allele frequencies. A latitudinal gradient of genetic components was observed, highlighting the transition from rhesus (north) to long-tailed macaque distribution (south) as well as the presence of one northern population of long-tailed macaques exhibiting unique genetic structure. Interspecific gene flow was estimated to have recently occurred after an isolation period, and the migration rate from rhesus to long-tailed macaques was slightly greater than in the opposite direction. Although some rhesus macaque-biased alleles have widely introgressed into long-tailed macaque populations, the inflection points of allele frequencies have been observed as concentrated around the traditionally recognized interspecific boundary where morphology discontinuously changed; this pattern was more pronounced in the X chromosome than in autosomes. Thus, due to geographic separation before secondary contact, reproductive isolation could have evolved, contributing to the maintenance of an interspecific boundary and species-specific morphological characteristics.

Increased Serum Malondialdehyde-Modified Low-Density Lipoprotein and Coronary Angiographic Progression After Drug-Eluting Stent Implantation in Patients With Stable Angina.

BACKGROUND: Cardiac events can occur after drug-eluting stent (DES) implantation due to coronary plaque progression at non-stented sites. Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is suggested to be an atherogenic marker. This study investigated the relationship between serum MDA-LDL and angiographic progression after DES implantation.Methods and Results:In total, 207 patients who underwent percutaneous coronary intervention (PCI) using DES and follow-up coronary angiography were retrospectively analyzed. MDA-LDL was serially measured before PCI and at follow up. Persistent high MDA-LDL was defined as a MDA-LDL level more than the median value both before PCI and at follow up. Angiographic progression was assessed by serial analysis of quantitative coronary angiography. Angiographic progression occurred in 35 patients (16.9%). MDA-LDL before PCI was significantly higher in the progression group than the non-progression group in all patients (143.4±35.8 U/L vs. 103.0±33.5U/L, P<0.001) and in patients with controlled LDL-cholesterol (LDL-C <100 mg/dL both before PCI and at follow up; 121.8±32.7 U/L vs. 84.9±24.9 U/L, P<0.001). There were positive correlations between % diameter stenosis changes and serum MDA-LDL before PCI in all patients (r=0.33, P<0.01) and those with controlled LDL-C (r=0.23, P=0.04). In multivariate logistic regression analysis, persistent high MDA-LDL was an independent predictor of plaque progression. CONCLUSIONS: Increased serum MDA-LDL was associated with angiographic progression after DES implantation.

Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex.

SAD kinases regulate presynaptic vesicle clustering and neuronal polarization. A previous report demonstrated that Sada-/- and Sadb-/- double-mutant mice showed perinatal lethality with a severe defect in axon/dendrite differentiation, but their single mutants did not. These results indicated that they were functionally redundant. Surprisingly, we show that on a C57BL/6N background, SAD-A is essential for cortical development whereas SAD-B is dispensable. Sada-/- mice died within a few days after birth. Their cortical lamination pattern was disorganized and radial migration of cortical neurons was perturbed. Birth date analyses with BrdU and in utero electroporation using pCAG-EGFP vector showed a delayed migration of cortical neurons to the pial surface in Sada-/- mice. Time-lapse imaging of these mice confirmed slow migration velocity in the cortical plate. While the neurites of hippocampal neurons in Sada-/- mice could ultimately differentiate in culture to form axons and dendrites, the average length of their axons was shorter than that of the wild type. Thus, analysis on a different genetic background than that used initially revealed a nonredundant role for SAD-A in neuronal migration and differentiation.

[Neutrophil-Lymphocyte Ratio as a Prognostic Indicator in Patients Treated with Nivolumab for Gastric Cancer].

BACKGROUND: Immune checkpoint inhibitors(nivolumab)have been recommended as third-line chemotherapy for advanced gastric cancer(AGC)according to the Guidelines of Gastric Cancer(5th edition). Therefore, they have been used in daily clinical practice. On the other hand, the neutrophil-lymphocyte ratio(NLR)has been reported to be associated with the prognosis of cancer patients. METHODS: Twenty patients treated with nivolumab for AGC between January 2018 and November 2019 were retrospectively examined. RESULTS: Median age of the 20 patients(18 males, 2 females)was 70 years(55- 84 years). Nivolumab was administered as second-, third-, fourth-, and fifth-line therapy in 1, 11, 7, and 1 case, respectively. The best tumor response evaluation was observed in PR 1, SD 7 and PD 10 cases. Median overall survival(OS)was 10 months, and median progression-free survival(PFS)was 3 months. No serious adverse events occurred. Compared to the NLR>2.0 group, OS significantly prolonged(2.2 months vs 21.9 months)and PFS tended to prolong(1.4 months vs 6.2 months)in the NLR≤2.0 group. CONCLUSION: NLR may be an effective prognostic factor in patients with AGC receiving nivolumab treatment.

The impact of intraday glucose variability on coronary artery spasm in patients with dysglycemia.

Impaired glucose metabolism is associated with an increased risk of cardiovascular complications, and coronary artery spasm is thought to underlie the development of coronary artery disease. Intraday glucose variability (GV) accelerates oxidative stress and inflammatory cytokine release, but its impact on coronary artery spasm remains unclear. This study investigated the relationship between intraday GV and coronary artery spasm. The study included 50 patients with dysglycemia and suspected coronary spastic angina. GV was analyzed by 24-h monitoring of the blood glucose concentration using a flash glucose monitoring system. The mean amplitude of glycemic excursion (MAGE) was calculated as an index of GV. Coronary artery spasm was assessed using the intracoronary acetylcholine provocation test. Coronary spasm was defined as acetylcholine-induced total or subtotal coronary occlusion. Changes in vessel diameter in response to acetylcholine were evaluated with quantitative coronary angiography. Coronary artery spasms were observed in 21 patients (42%). MAGE was significantly higher in patients with spasms compared to those without spasms (127.5 ± 33.5 vs. 91.4 ± 37.6, p < 0.01). Regression analysis showed a positive correlation between MAGE levels and coronary diameter changes induced by acetylcholine (r = 0.47, p < 0.01). In multiple regression analysis, MAGE was independently associated with acetylcholine-induced coronary diameter change (ß = 0.47, p < 0.01). Intraday GV was associated with coronary artery spasm in patients with dysglycemia.

An extraskeletal osteosarcoma in the auricle of a Wistar Hannover rat.

An extraskeletal osteosarcoma was detected in the auricle of a 110-week-old female Wistar Hannover rat. Grossly, the tumor, measuring 15 mm in size, was observed in the subcutis as a solid and hard mass. Histologically, the majority of the mass comprised mature, compact bone. It was surrounded by neoplastic cells showing a variety of histologies, such as sarcoma, not otherwise specified, and myxosarcoma away from the bone-forming region. However, these different histological regions were considered to be components of a single bone tumor, based on the common expression of osterix and a similar mixture of constituent cells in each region. The tumor was diagnosed as an extraskeletal osteosarcoma because of the presence of infiltrative growth and abnormal mitosis and its development in the auricle without attachment to the skeleton. The present case is a rare histological type of an extraskeletal osteosarcoma with independent and different histological elements in rats.

Phylogenetic relationship of a fossil macaque (Macaca cf. robusta) from the Korean Peninsula to extant species of macaques based on zygomaxillary morphology.

Little is known about the biogeographical and evolutionary histories of macaques (Macaca spp.) in East Asia because the phylogenetic positions of fossil species remain unclear. Here we examined the zygomaxillary remains of a fossil macaque (M. cf. robusta) from the Durubong Cave Complex, South Korea, that dates back to the late Middle to Late Pleistocene, to infer its phylogenetic relationship to extant species. We took 195 fixed- and semi-landmarks from the zygomaxillary regions of the fossil specimen and from 147 specimens belonging to 14 extant species. We then conducted a generalized Procrustes analysis followed by a multivariate statistical analysis to evaluate the phenetic affinities of the fossil to the extant species and reconstructed the most parsimonious phylogenetic tree using a phylogenetic morphometric approach. We found that the fossil was most similar to Macaca fuscata (Japanese macaque) in the zygomaxillary morphospace although it was at the limit of the range of variation for this species. The second closest in the morphospace was the continental Macaca mulatta (rhesus macaque). Parsimonious reconstruction confirmed that the fossil was most closely related to M. fuscata, even after controlling for the effects of allometry. These findings suggest that in the late Middle to Late Pleistocene, close relatives of M. fuscata that looked like the extant species were distributed on the Korean Peninsula, where no species of macaques are found today. Thus, some morphological characteristics of M. fuscata may have developed before its ancestor dispersed into the Japanese archipelago.

Impact of malondialdehyde-modified low-density lipoprotein on coronary plaque vulnerability in patients not receiving lipid-lowering therapy: a whole coronary analysis with multislice-computed tomography.

Vulnerable plaque disruption was suggested as a primary cause of acute coronary syndrome. This study investigated the impact of malondialdehyde-modified low-density lipoprotein (MDA-LDL) on whole coronary plaque vulnerability, based on multislice-computed tomography (MSCT). We included 197 patients that were not receiving lipid-lowering therapy. We retrospectively analyzed MSCT and MDA-LDL measurements. We defined a CT-derived vulnerable plaque as a plaque with a remodeling index > 1.10 and a mean CT density value < 30 HU. Vulnerable plaques were detected in 60 patients (30%). Patients with vulnerable plaques had significantly higher MDA-LDL levels than patients without vulnerable plaques (151.3 ± 42.3 vs. 118.5 ± 41.7 U/L, p < 0.01). A univariate regression analysis showed that vulnerable plaques were significantly related to MDA-LDL levels [10 U/L groups, odds ratio (OR): 1.19; p < 0.01] and in a multivariate model (10 U/L groups, OR: 1.18; p < 0.01). Patients with multivessel vulnerable plaques had significantly higher MDA-LDL levels than those with single-vessel involvement or no vulnerable plaque (172.4 ± 28.5 vs. 142.8 ± 44.2 vs. 118.5 ± 41.7 U/L, respectively; p < 0.01). MDA-LDL difference was observed for all LDL tertiles (bottom; 128.9 ± 41.1 vs. 97.3 ± 25.0 U/L, p < 0.01, middle; 142.6 ± 42.7 vs. 122.5 ± 35.1 U/L, p = 0.05, top; 166.0 ± 38.1 vs. 143.5 ± 51.6 U/L, p = 0.05). Increased MDA-LDL levels were associated with the presence and extent of vulnerable plaques, regardless of LDL levels.

Spontaneous malignant myoid thymoma in an aged female Fischer 344 rat.

A whitish mass approximately 30 mm in diameter was noted in the anterior mediastinum of a 67-week-old female Fischer 344 rat. Histopathologically, two types of tumor cells were identified on the basis of morphologic features: epithelial tumor cells with a tubular or cord-like growth pattern and rhabdomyosarcomatous tumor cells characterized by the presence of cross-striations. Immunohistochemically, the epithelial tumor cells reacted positively for cytokeratin AE1/AE3, and some reacted positively for p63, which is expressed in normal thymic epithelial cells. The rhabdomyosarcomatous tumor cells stained positively for desmin, sarcomeric actin, and S-100 protein, which coincides with the stainability of normal thymic myoid cells. Since the tumor was also found to have malignant features such as high proliferative activity, cytologic atypia, and necrotic behavior, it was diagnosed as a malignant myoid thymoma. We believe that this is the first case report of such a tumor in a rodent.

Quantitation of nasal development in the early prenatal period using geometric morphometrics and MRI: a new insight into the critical period of Binder phenotype.

OBJECTIVES: Disturbance of the development of the nasal septum in the early prenatal period causes congenital facial anomalies characterized by a flat nose and defects of the anterior nasal spine (ANS), such as Binder phenotype. The present research aimed to assess the development of the nasal septum and the ANS with growth in the early prenatal period. METHODS: Magnetic resonance images were obtained from 56 specimens. Mid-sagittal images were analyzed by using geometric morphometrics for the development of the nasal septum, and angle analysis was performed for the development of the ANS. Additionally, we calculated and visualized the ontogenetic allometry of the nasal septum. RESULTS: Our results showed that the nasal septum changed shape in the anteroposterior direction in smaller specimens, while it maintained an almost isometric shape in larger specimens. Furthermore, mathematical evidence revealed that the maturation periods of the shapes of the ANS and the nasal septum were around 12 and 14 weeks of gestation, respectively. CONCLUSION: The anteroposterior development of the nasal septum is specific until 14 weeks of gestation, and it is important for nasal protrusion and the development of the ANS. Therefore, the disturbance of such development could induce low nasal deformity, including Binder phenotype. © 2017 John Wiley & Sons, Ltd.