Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.

Influence of different physiological hemodynamics on fractional flow reserve values in the left coronary artery and right coronary artery.

BACKGROUND: Although the left coronary artery (LCA) has a flow profile in that most blood flow occurs during diastole rather than systole, the right coronary artery (RCA) has a flow pattern that is less diastolic dominant. This study assessed whether coronary pressure waveforms distal to stenoses with the same fractional flow reserve (FFR) was the same between the LCA and RCA. METHODS: A total of 347 vessels from 318 patients who underwent FFR measurements were included. Conventional FFR was calculated as the ratio of the mean coronary distal pressure (Pd) to the mean aortic pressure (Pa) at maximal hyperemia. The pressure drop ratios in systole (PDRsystole) and diastole (PDRdiastole) were calculated as the sum of (Pa minus Pd) divided by the sum of Pa at the intracoronary diastolic and systolic pressure phases, respectively. RESULTS: Analysis of covariance of the regression line of correlation between conventional FFR and PDRsystole revealed that the slope was significantly greater in the RCA than in the left anterior descending artery (LAD) and left circumflex artery (LCX) (-0.765, -0.578, and -0.589, p < 0.001). On the other hand, the regression line of correlation between conventional FFR and PDRdiastole found that the slope was significantly greater in the LAD and LCX than in the RCA (-1.349, -1.318, and -1.223, p < 0.001). CONCLUSIONS: The pressure waveform distal to the stenosis differs between the LCA and RCA. In the LCA, the decrease in diastolic pressure mainly contributed to the drop in FFR, whereas in the RCA, it was the decrease in systolic pressure.

A Short-Duration Combined Exercise and Education Program to Improve Physical Function and Social Engagement in Community-Dwelling Elderly Adults.

Exercise is a key intervention for improving older adults' physical function and life expectancy. Here, we investigated a short-term intervention program designed to improve the physical functioning of elderly adults in a community-dwelling setting. We examined the effect of a 5-week combined exercise and education program on the physical function, social engagement, mobility performance, and fear of falling in 42 subjects older than 65 years. Eleven subjects dropped out. There was significant improvement in the 30-second chair stand test (p < .001) and timed up-and-go test (p < .001) between the baseline and the last session. At the end of the intervention, the subjects' social engagement was significantly higher than at baseline (p = .022), but this improvement was not maintained in the follow-up assessment. These results suggest that a combined exercise and education program can improve the physical function and social engagement of elderly individuals living in a community dwelling.

A case of malignant rhabdoid tumor mimicking yolk sac tumor.

Malignant rhabdoid tumors (MRTs) are rare, highly aggressive embryonal neoplasms caused by biallelic alterations of the SMARCB1 gene. MRTs may occur in any soft tissue, but extracranial extrarenal MRTs are extremely rare. Diagnosis of MRTs in unusual locations and with an uncharacteristic cytomorphology that mimics other tumors is difficult. This was an atypical case of MRT in a 15-year-old female with tumors that closely resembled yolk sac tumors. It was extremely challenging to diagnose the tumors without confirming the SMARCB1 status.

A case of an elderly hip disarticulation amputee with rheumatoid arthritis who regained the ability to walk using a hip prosthesis.

[Purpose] We report a case of an elderly patient with rheumatoid arthritis who underwent hip disarticulation because of necrotizing fasciitis and regained the ability to walk independently with a prosthetic limb. [Participant and Methods] A 61-year-old female patient underwent right hip disarticulation due to severe necrotizing fasciitis of the right lower limb. Her chief complaint was that she was not able to walk inside her house or outdoors to perform instrumental activities of daily living. We applied a Canadian-type hip disarticulation prosthesis to the stump. The patient received in-hospital physical therapy, occupational therapy, and clinical psychology counselling for 145 days. As her hands and fingers were weakened by rheumatism, we made several modifications to the prosthesis to enable the patient to attach and detach it independently. [Results] The patient was able to use the prosthesis to walk continuously for 45 m, perform various housework duties, drive a car, and go out, thus accomplishing the desired daily activities. [Conclusion] Our patient, an elderly hip disarticulation amputee with rheumatoid arthritis, was able to walk independently using a prosthetic limb. The application of prosthetic limbs may be appropriate even for hip disarticulation amputees with comorbidities that make it difficult to acquire a prosthetic gait.

Heparin Induces the Mobilization of Heart-Derived Multipotent Mesoangioblasts During Cardiac Surgery With Cardiopulmonary Bypass or Cardiac Catheterization.

BACKGROUND: We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that express cardiac mesodermal markers, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). We also found that hepatocyte growth factor (HGF) is upregulated during cardiac surgery with CPB in humans, and induces MAB-like cell mobilization in rodents. These results strongly suggest that heparin induced MAB mobilization via HGF upregulation. Here, we tested this hypothesis in patients undergoing cardiac surgery or cardiac catheterization. We also examined whether human cMABs are derived from the heart.Methods and Results:Plasma HGF levels were determined by ELISA. Mononuclear cells isolated from blood samples were cultured on fibronectin-coated dishes, and outgrowing cMAB colonies were counted. We first confirmed that HGF upregulation and cMAB mobilization were observed before the start of CPB, excluding the possibility that CPB is the primary inducer of cMAB mobilization. We then examined patients undergoing cardiac catheterization and found that heparin significantly increased plasma HGF levels and the number of cMAB colonies in a dose-dependent manner. The results of simultaneous blood sampling from the aortic sinus, coronary sinus, and right atrium were consistent with the notion that human cMABs are derived from the heart. CONCLUSIONS: Human cMABs are mobilized by heparin injection during cardiac surgery or cardiac catheterization, presumably via HGF upregulation.

Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities.

A growing number of studies suggest critical tumor suppressor roles of the SWI/SNF chromatin remodeling complex in a variety of human cancers. The recent discovery of SMARCA4-deficient thoracic sarcomas has added to the list of tumor groups with the SMARCA4 inactivating mutation. To better characterize these tumors and establish their nosological status, we undertook a clinicopathological and molecular analysis of 12 SMARCA4-deficient thoracic sarcomas and compared them with three potentially related disease entities. Eleven men and one woman with SMARCA4-deficient thoracic sarcomas (aged 27-82 years, median 39 years) were included in the study. Most of the patients had heavy smoking exposure and pulmonary emphysema/bullae. The primary tumors were large and involved the thoracic region in all cases and simultaneously affected the abdominal cavity in 3 cases. The patients followed a rapid course, with a median survival of 7 months. Histologically, all tumors showed diffuse sheets of mildly dyscohesive, relatively monotonous, and undifferentiated epithelioid cells with prominent nucleoli. Immunohistochemically, all tumors demonstrated a complete absence (8 cases) or diffuse severe reduction (4 cases) of SMARCA4 expression. Cytokeratin, CD34, SOX2, SALL4, and p53 were expressed in 6/12, 10/12, 10/12, 10/12, and 7/10 cases, respectively. SMARCA2 expression was deficient in 11/12 cases, and none (0/8) expressed claudin-4. Targeted sequencing was performed in 5 cases and demonstrated the inactivating SMARCA4 mutation in each case and uncovered alterations in TP53 (5/5), NF1 (2/5), CDKN2A (2/5), KRAS (1/5), and KEAP1 (1/5), among others. Comparative analysis supported the distinctiveness of SMARCA4-deficient thoracic sarcomas as they were distinguishable from 13 malignant rhabdoid tumors, 15 epithelioid sarcomas, and 12 SMARCA4-deficient lung carcinomas based on clinicopathological and immunohistochemical grounds. SMARCA4-deficient thoracic sarcomas constitute a unique, highly lethal entity that requires full recognition and differentiation from other epithelioid malignancies involving the thoracic region.

Prostaglandin E-major Urinary Metabolite as a Biomarker for Pediatric Ulcerative Colitis Activity.

OBJECTIVES: Prostaglandin E-major urinary metabolite (PGE-MUM) is a useful biomarker for adult ulcerative colitis (UC) activity. In the present study, we evaluated whether PGE-MUM can also be a biomarker of pediatric UC activity and compared its efficacy in predicting UC activity with that of C-reactive protein and erythrocyte sedimentation rate. METHODS: Twenty-nine pediatric patients with UC (8-18 years) and 29 healthy age- and sex-matched subjects were enrolled. UC activity was evaluated using the Pediatric Ulcerative Colitis Activity Index, highest Mayo endoscopic scoring (Mayo), and Matts grading (Matts) for histologic scoring, and the sum of Mayo (total of 6 segments) and Matts in all patients with UC. PGE-MUM levels were measured using a radioimmunoassay. RESULTS: PGE-MUM levels were elevated in endoscopically and histologically active UC patients, but not in patients with endoscopic and histologic remission or controls. PGE-MUM levels positively and significantly correlated with UC activity. PGE-MUM levels were positively correlated with Pediatric Ulcerative Colitis Activity Index (r = 0.594), highest Mayo (r = 0.462), the sum of Mayo (r = 0.694), and the sum of Matts (r = 0.613), but not with highest Matt (r = 0.352). The sum of Mayo and the sum of Matts, which reflect total colon inflammation, showed highest correlation with PGE-MUM. C-reactive protein levels did not correlate with any UC activity scores. Erythrocyte sedimentation rate exhibited correlation (r = 0.490) with the sum of Mayo only. CONCLUSIONS: PGE-MUM is a reliable biomarker that reflects both the endoscopic and histologic activity of the entire colon in pediatric UC.

Reclassification of rhabdoid tumor and pediatric undifferentiated/unclassified sarcoma with complete loss of SMARCB1/INI1 protein expression: three subtypes of rhabdoid tumor according to their histological features.

Rhabdoid tumor is characterized by rhabdoid cells and shows complete loss of SMARCB1/INI1 protein expression. In existing classifications, the diagnostic synonyms vary depending on the anatomic site: rhabdoid tumors in the central nervous system or extra-central nervous system are, respectively, classified as atypical teratoid/rhabdoid tumor or malignant rhabdoid tumor. In this study, we analyzed the histological, immunohistochemical, microRNA, and clinicopathological statuses of tumors initially diagnosed as malignant rhabdoid tumor (n=33), atypical teratoid/rhabdoid tumor (n=11), and pediatric undifferentiated/unclassified sarcoma (n=8) with complete loss of SMARCB1/INI1 expression, and considered the possibility of their histological reclassification. Our analysis indicated that the tumors could be histologically reclassified into three groups: conventional-type tumors resembling malignant rhabdoid tumor, atypical teratoid/rhabdoid-type tumors resembling atypical teratoid/rhabdoid tumor, and small cell-type tumors resembling malignant lymphoma. The reclassified conventional type was composed of 27 malignant rhabdoid tumors and 9 atypical teratoid/rhabdoid tumors (36 cases). The atypical teratoid/rhabdoid type consisted of six malignant rhabdoid tumors, two atypical teratoid/rhabdoid tumors, and two undifferentiated/unclassified sarcomas (10 cases). The six cases of small cell type were made up of six undifferentiated/unclassified sarcomas. All of the available tumor specimens were positive for vimentin and epithelial marker (EMA, CAM5.2, or AE1/AE3). MicroRNA profiles were not significantly different between the conventional- and small cell-type tumors (Pearson's correlation coefficient: 0.888300 or 0.891388). There was no significant difference in overall survival between atypical teratoid/rhabdoid tumor and malignant rhabdoid tumor (P=0.16). In addition, there were no significant differences in survival between any of the reclassified combinations. In conclusion, we could classify eight tumors initially diagnosed as undifferentiated/unclassified sarcomas into two cases of atypical teratoid/rhabdoid type and six cases of small cell type. We suggest that reclassification of malignant rhabdoid tumors into three groups according to their histologic features rather than the traditional classification by sites of origin would be favorable for their histopathological diagnosis.

Low Frequency of Programmed Death Ligand 1 Expression in Pediatric Cancers.

Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway blockade has become a promising therapeutic target in adult cancers. We evaluated PD-L1 expression and tumor-infiltrating CD8(+) T cells in formalin-fixed, paraffin-embedded tumor specimens from 53 untreated pediatric patients with eight cancer types: neuroblastoma, extracranial malignant germ cell tumor, hepatoblastoma, germinoma, medulloblastoma, renal tumor, rhabdomyosarcoma, and atypical teratoid/rhabdoid tumor. One rhabdomyosarcoma with the shortest survival exhibited membranous PD-L1 expression and germinoma contained abundant tumor-infiltrating CD8(+) T cells and PD-L1-positive macrophages. The PD-1/PD-L1 pathway tended to be inactive in pediatric cancers.

Differential SALL4 immunoexpression in malignant rhabdoid tumours and epithelioid sarcomas.

AIMS: Malignant rhabdoid tumours (MRTs) and epithelioid sarcomas (ESs) are distinctive malignant neoplasms with characteristic clinicopathological features. However, these two tumour types share some phenotypic features, such as epithelioid/rhabdoid cytology, expression of epithelial markers, and immunohistochemical loss of INI1. The distinction can be problematic in atypical clinical settings, and ancillary diagnostic tools are needed. The expression of CD34 is widely cited as favouring the diagnosis of ES, but no formal comparative study has been performed in the post-INI1 era. Here, we evaluated the utility of SALL4 for differentiating MRTs from ESs, and compared its performance with that of CD34. METHODS AND RESULTS: Fifteen MRTs and 36 ESs were retrieved. All MRTs and ESs lacked INI1 reactivity, except for one MRT that lacked BRG1. A representative slide from each case was stained using antibodies against SALL4 and CD34. Ten (67%) of the 15 MRTs expressed SALL4. In contrast, only one (3%) of the 36 ESs expressed SALL4. CD34 staining was observed in nine (60%) of the MRTs and 29 (81%) of the ESs. CONCLUSIONS: Despite moderate sensitivity, SALL4 expression may aid in distinguishing MRTs from ESs. CD34 was found to have questionable utility in making such distinctions.

Laparoscopic-assisted pancreaticoduodenectomy in a child with gastrinoma.

Gastrinoma is rare in children. We report the case of a 9-year-old boy with weight loss and vomiting. Upper gastrointestinal imaging showed severe stenosis of the duodenum. Although gastrin was very high, imaging did not show a gastrinoma. Selective arterial secretagogue injection (SASI) test indicated a tumor within the gastroduodenal arterial zone. In accordance with the SASI test result, we performed laparoscopic-assisted pancreaticoduodenectomy (LAPD). Postoperative biochemistry confirmed complete resection of the gastrinoma, and the patient was asymptomatic at follow up, 30 months after surgery. Even in patients with negative imaging for gastrinoma, aggressive resection following accurate localization on SASI test is biochemically curative. In such cases, the tumor is probably very small and LAPD may offer a minimally invasive procedure. As far as we know, LAPD in a child has not been previously reported.

Effect of chair stand exercise on activity of daily living: a randomized controlled trial in hemodialysis patients.

OBJECTIVE: Muscle atrophy and weakness impair activity of daily living (ADL). We examined whether chair stand exercise can improve ADL of hemodialysis patients. DESIGN: A randomized controlled trial. SETTING AND PARTICIPANTS: A single center study. SUBJECTS: Outpatients on hemodialysis older than 60 years (61-79 years). INTERVENTION: Twelve weeks of intervention with chair stand exercise, 3 sessions/week versus the control exercise (stretch, 1 session/week). MAIN OUTCOME MEASURE: The primary outcome was the change in functional independence measure (FIM) score from baseline. The secondary outcomes were changes in thigh circumference, muscle strength of quadriceps, 6-minute walking distance, maximum duration of chair stand exercise, health-related quality of life, cognitive function serum albumin, and hemoglobin. RESULTS: Among the 27 patients who were randomized, 17 completed the study. The change in FIM from baseline was greater in the intervention group (1 [1-3] vs. 0 [0-0], median (minimum to maximum), P < .001) due to the significant improvement in the FIM subscales related to mobility (bed/chair/wheel chair) and locomotion (stair). Among the secondary outcomes, significant difference was noticed in the changes in thigh circumference and the physical component summary score of health-related quality of life by Medical Outcome Study 36-Item Short-Form Health Survey (SF-36v2). CONCLUSIONS: Chair stand exercise improved ADL in the hemodialysis patients aged older than 60 years.

Long-term follow-up results of the observation program for neuroblastoma detected at 6-month mass screening.

We conducted an observation program of neuroblastoma in infants, detected by mass screening at 6 months of age; we followed up with them for 15 years. No recurrence was observed after disappearance of tumors, and persistent tumors showed no malignant transformation or metastasis. Histology of the resected tumors showed age-related differentiation.

Full-thickness small intestine necrosis with midgut volvulus, distributed in a patchy fashion, is reversible with moderate blood flow: resumption of normal function to non-viable intestine.

Midgut volvulus is a highly life-threatening condition that carries a high risk of short gut syndrome. We report a case of catastrophic neonatal midgut volvulus in which second-look laparotomy revealed apparently non-viable remnant small intestine but with a moderate blood supply. Full-thickness small intestine necrosis was distributed in a patchy fashion, with non-viable and necrotic areas distributed so widely that no portion of the intestine could be resected. A section of full-thickness necrotic intestine preserved at surgery was able to regenerate, and normal function was restored over a period of 1 month. This case indicated that intestinal resumption may be dependent on blood flow. Even when intestinal viability is questionable, preservation enables the chance of regeneration if moderate blood flow is present.

Intensive Care Unit Nurses' Professional Autonomy: A Scoping Review.

Intensive care unit (ICU) nurses' professional autonomy is a critical factor affecting their ability to sustainably provide high-quality care to patients who are critically ill and to their families. However, in the absence of a systematic or scoping review of ICU nurses' professional autonomy, limited information and evidence are available on this topic. The aim of this scoping review was to clarify the extent and type of evidence on ICU nurses' professional autonomy. This scoping review was conducted in accordance with the Joanna Briggs Institute methodology for scoping reviews. The following research questions were addressed: (1) Which areas of interest and trends regarding ICU nurses' professional autonomy have been explored in studies published in scientific journals? And (2) What is known about ICU nurses' professional autonomy? The data sources included MEDLINE, CINAHL Ultimate, PsycINFO, Cochrane Library, and Ichushi-Web of the Japan Medical Abstracts Society databases. Identified studies were mapped based on their aim, design, methodology, and key findings and categorized according to their focus areas. Of the 734 identified studies, 16 were analyzed. The identified categories were as follows: "relationship between professional autonomy and mental issues," "experiences and processes of exercising professional autonomy," "relationship between professional autonomy and nurse-physician collaboration," "relationship between professional autonomy and demographic characteristics," "concept of professional autonomy," "barriers to professional autonomy," and "team approach to improve professional autonomy." Most studies have focused on the relationship between professional autonomy and mental health issues and nurse-physician collaboration and few included interventions to enable or promote the exercise of professional autonomy, highlighting a research gap. Future research should identify factors that inhibit the professional autonomy of ICU nurses and that can be changed through interventions and should develop educational and organizational change-based interventions to modify the factors.

Aggressive transformation of juvenile myelomonocytic leukemia associated with duplication of oncogenic KRAS due to acquired uniparental disomy.

A small fraction of cases of juvenile myelomonocytic leukemia (JMML) develop massive disease activation. Through genomic analysis of JMML, which developed in an individual with mosaicism for oncogenic KRAS mutation with rapid progression, we identified acquired uniparental disomy at 12p. We demonstrated that duplication of oncogenic KRAS is associated with rapid JMML progression.

Kasabach-Merritt phenomenon: a report of 11 cases from a single institution.

BACKGROUND: Kasabach-Merritt phenomenon (KMP) is a rare condition and optimal treatments have not yet been established, especially for cases that are unresponsive to first-line therapy. We retrospectively reviewed 11 KMP cases treated over the past 13 years in our institute. OBSERVATIONS: With the exception of 1 case, steroids were administered as the first-line therapy. Eight cases required second-line or third-line therapy. The effective salvage therapies include interferon (n=1), radiotherapy (n=1), and chemotherapy (n=5). One case continues to depend upon chemotherapy. Three refractory cases were therapy dependent over 1 year of age, whereas 8 were treated effectively by 6 months of age. CONCLUSIONS: Chemotherapy seems to be the most effective therapy for steroid-resistant KMP cases.