In- and out-of-hospital outcomes following surgical stabilization of rib fractures in 80 years and older: A single-institution experience.

BACKGROUND: Surgical stabilization of rib fractures (SSRF) has demonstrated benefit in patients with flail chest and multiple displaced fractures. There is mounting evidence for SSRF following chest wall injury (CWI) for the geriatric trauma population. A recent multi-center retrospective study highlighted a mortality benefit even for those patients aged 80 years and older. The objective of this investigation was to review our institutional experience with both in- and out-of-hospital outcomes within this patient population following SSRF. METHODS: A retrospective review of patients 80 years and older was performed at a high-volume level 2 trauma center from 2017 to 2021. SSRF volume is routinely >60 cases per year. Perioperative, inpatient, and outpatient data were collected as available. Primary outcomes were inpatient and 90-day mortality. Secondary outcomes included discharge on narcotics and freedom from narcotics at 30 days. RESULTS: 50 patients were included for review. Mean age was 86 years and mechanism of injury was most often fall. 28 of 50 (56%) patients had flail chest (radiographic). Mean number of ribs fixated was 4.7 and time to surgery 2.5 days. Inpatient mortality was 3/50 (6%), 90-day mortality was 9/50 (18%) of which three were attributable primarily to CWI (6/50, 12%). Of patients with follow-up of 1 year and beyond, 27/28 were alive (96%). With respect to narcotic consumption, 45% (21/47) were discharged on narcotics with 90% (28/31; N limited by missing data) being narcotic-free at 30 days. CONCLUSION: In this high-risk patient population, inpatient mortality was comparably low to prior reports, though 90-day mortality was doubled when incorporating CWI-related deaths. Narcotic use was seen in the minority of patients upon discharge, and most progressed to being narcotic-free at 30 days post-hospitalization. Inpatient outcomes alone may not adequately define both the benefit and risk of SSRF performed in patients 80 years and older.

Apigenin attenuates tetrabromobisphenol A-induced cytotoxicity in neuronal SK-N-MC cells.

Tetrabromobisphenol A (TBBPA) is a reactive brominated flame retardant widely used in various industrial and household products. This compound is persistent in the environment and accumulates in living organisms through the food chain, and is toxic to animals and human beings. Studies have shown that TBBPA is toxic to various human cell lines, including neuronal cells. Apigenin is a dietary flavonoid that exhibits various beneficial health effects on biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated the cytoprotective effects of apigenin against TBBPA-mediated cytotoxicity in SK-N-MC cells. Our results demonstrated that treatment of SK-N-MC cells with apigenin increased the cell viability, which was decreased by TBBPA, and reduced apoptosis and autophagy induced by TBBPA. Although we did not observe any change in the levels of IL-1ß and nitrite in cultured cells after TBBPA treatment, apigenin was found to decrease the production of these pro-inflammatory mediators. Apigenin decreased the intracellular Ca2+ concentration, NOX4 level, oxidative stress, and mitochondrial membrane potential loss and increased the mitochondrial biogenesis and nuclear Nrf2 levels that were reduced by TBBPA. Finally, apigenin treatment decreased Akt and ERK induction in cells exposed to TBBPA. Based on these results, apigenin could be a promising candidate for designing natural drugs to treat or prevent TBBPA-related neurological disorders.

HER2 Expression in Peritoneal Dissemination of High-Grade Serous Ovarian Carcinoma: A Comparative Study of Immunohistochemical Reactivity Using Four HER2 Antibodies.

Most high-grade serous ovarian carcinomas (HGSOCs) involving the peritoneum are aggressive. Epidermal growth factor receptor 2 (HER2) is aberrantly activated in a variety of solid cancers. The HER2 status of a tumor is based on cytoplasmic membrane staining of an intracellular domain (ICD)-specific HER2 antibody. We compared four anti-HER2 antibodies in an immunohistochemical study of HGSOC with peritoneal dissemination. HER2 expression was assessed in peritoneal disseminated HGSOC specimens from 38 patients by immunohistochemistry using four different anti-HER2 antibodies (an ICD antibody (clone A0485), an extracellular domain (ECD) antibody (clone SP3), and two antibodies recognizing HER2 phosphorylated at tyrosine 877 or 1248 (pHER2Y877 and pHER2Y1248)). HER2 gene amplification was accessed by chromogenic in situ hybridization (CISH). The antibodies showed HER2 positivity as follows: 31.6% of cases (12/38) with A0485, 26.3% (10/38) with SP3, 7.9% (3/38) with pHER2Y877, and 21.1% (8/38) with pHER2Y1248. Fifteen out of thirty-eight (39.5%) cases were positive for at least one of the four HER2 antibodies. HER2 gene amplification was detected in 3/19 cases. All four HER2 antibodies could be used for patient selection for anti-HER2 therapies. These findings raise the possibility of anti-HER2 therapeutic strategies for HGSOC with peritoneal dissemination.

Cytopathologic features of human papillomavirus-independent, gastric-type endocervical adenocarcinoma.

BACKGROUND: Gastric-type endocervical adenocarcinoma (GEA) is unrelated to human papillomavirus (HPV) infection and is clinically aggressive compared with HPV-associated usual-type endocervical adenocarcinoma (UEA). The cytological diagnosis falls short of a definitive diagnosis of GEA and is often categorized as atypical glandular cells (AGCs). To improve cytologic recognition, cytological findings of HPV-independent GEA were analyzed and the results compared with HPV-associated UEA. METHODS: Cervical Papanicolaou (Pap) smears from eight patients with a histopathologic diagnosis of GEA and 12 control cases of UEA were reviewed. All slides were conventionally prepared and/or liquid-based prepared (ThinPrep) and stained following the Pap method. A mucinous background, architectural, nuclear, and cytoplasmic features were analyzed and compared with UEA. RESULTS: Preoperative cytologic diagnoses of the eight GEA cases were AGCs, favor neoplastic in three cases, adenocarcinoma in situ in one case, and adenocarcinoma in four cases. Cytologically, monolayered honeycomb-like sheets (p = .002) of atypical endocervical cells with vacuolar granular cytoplasm (p = .001) were extensive in GEA, and three-dimensional clusters (p = .010) were extensive in UEA. Although the differences were not statistically significant, background mucin (p = .058), vesicular nuclei (p = .057), and golden-brown intracytoplasmic mucin (p = .089) were also discriminatory findings for GEA versus UEA. CONCLUSIONS: Although GEA is difficult to diagnose on cytologic screening, GEA can be recognized based on cytologic features of monolayered honeycomb sheets of atypical endocervical cells with abundant vacuolar cytoplasm and some golden-brown intracytoplasmic mucin. UEA cases are characterized by three-dimensional clusters.

Characterization of Poorly Cohesive and Signet Ring Cell Carcinomas and Identification of PTPRM as a Diagnostic Marker.

Background and aims. Signet ring cell (SRC) and poorly cohesive (PC) gastric carcinomas are morphologically similar but exhibit different biological behavior. We compared the clinical and molecular characteristics of SRC and PC carcinomas. Methods. Diffuse-type gastric cancer (GC) cases were classified into SRC carcinomas (>90% of SRCs), PC carcinomas (<10% of SRCs), and combined PC/SRC carcinomas (≤90% but ≥10% of SRCs). The gene expression patterns in SRC and PC carcinomas were examined by transcriptome and protein immunohistochemistry analyses, and diagnostic and prognostic biomarkers were identified. Results. SRC and PC carcinomas showed significantly different clinical behaviors but shared common RNA expression patterns. PC carcinomas showed an increased expression of genes related to cancer progression. Among genes differentially expressed between PC and SRC carcinomas, protein tyrosine phosphatase receptor type M (PTPRM) was overexpressed in PC and related to unfavorable clinical factors. Conclusion. We found that PC and SRC carcinomas had distinct clinical characteristics and should be classified as different carcinoma types. PTPRM was identified as a potential diagnostic and prognostic biomarker for PC carcinomas and could represent a potential therapeutic target.

Whole-exome sequencing reveals rare genetic variations in ovarian granulosa cell tumor.

Ovarian granulosa cell tumor (OGCT) is a rare ovarian tumor that accounts for about 2-5% of all ovarian tumors. Despite the low grade of ovarian tumors, high and late recurrences are common in OGCT patients. Even though this tumor usually occurs in adult women with high estrogen levels, the cause of OGCT is still unknown. To screen genetic variants associated with OGCT, we collected normal and matched-tumor formalin-fixed paraffin-embedded (FFPE) from 11 OGCT patients and performed whole-exome sequencing (WES) using Illumina NovaSeq 6000. A total of 1,067,219 single nucleotide polymorphisms (SNPs) and 162,155 insertions/deletions (indels) were identified from 11 pairs of samples. Of these, we identified 44 tumor-specific SNPs in 22 genes and four tumor-specific indels in one gene that were common to 11 patients. We used three cancer databases (TCGA, COSMIC, and ICGC) to investigate genes associated with ovarian cancers. Nine genes (SEC22B, FEZ2, ANKRD36B, GYPA, MUC3A, PRSS3, NUTM2A, OR8U1, and KRTAP10-6) associated with ovarian cancers were found in all three databases. In addition, we identified seven rare variants with MAF ≤ 0.05 in two genes (PRSS3 and MUC3A). Of seven rare variants, five variants in MUC3A are potentially pathogenic. Furthermore, we conducted gene enrichment analysis of tumor-specific 417 genes in SNPs and 106 genes in indels using cytoscape and metascape. In GO analysis, these genes were highly enriched in "selective autophagy", and "regulation of anoikis". Taken together, we suggest that MUC3A is implicated in OGCT development, and MUC3A could be used as a potential biomarker for OGCT diagnosis.

Surgical stabilization of severe chest wall injury following cardiopulmonary resuscitation.

BACKGROUND: Cardiopulmonary resuscitation (CPR) contributes to significant chest wall injury similar to blunt trauma. With benefits realized for surgical stabilization of rib fractures (SSRFs) for flail injuries and severely displaced fractures following trauma, SSRF for chest wall injury following CPR could be advantageous, provided good functional and neurologic outlook. Experience is limited. We present a review of patients treated with SSRF at our institution following CPR. METHODS: A retrospective analysis of patients undergoing SSRF following CPR was performed between 2019 and 2020. Perioperative inpatient data were collected with outpatient follow-up as able. RESULTS: Five patients underwent SSRF over the course of the 2-year interval. All patients required invasive ventilation preoperatively or had impending respiratory. Mean age was 59 ± 12 years, with all patients being male. Inciting events for cardiac arrest included respiratory, ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, and anaphylaxis. Time to operation was 6.6 ± 3 days. Four patients demonstrated anterior flail injury pattern with or without sternal fracture, with one patient having multiple severely displaced fractures. Surgical stabilization of rib fracture was performed appropriately to restore chest wall stability. Mean intensive care unit length of stay was 9.8 ± 6.4 days and overall hospital length of stay 24.6 ± 13.2 days. Median postoperative ventilation was 2 days (range, 1-15 days) with two patients developing pneumonia and one requiring tracheostomy. There were no mortalities at 30 days. One patient expired in hospice after a prolonged hospitalization. Disposition destination was variable. No hardware complications were noted on outpatient follow-up, and all surviving patients were home. CONCLUSION: Chest wall injuries are incurred frequently following CPR. Surgical stabilization of these injuries can be considered to promote ventilator liberation and rehabilitation. Careful patient selection is paramount, with surgery offered to those with reversible causes of arrest and good functional and neurologic outcome. Experience is early, with further investigation needed. LEVEL OF EVIDENCE: Therapeutic, Level V.

Protective effects of sciadopitysin against methylglyoxal-induced degeneration in neuronal SK-N-MC cells.

The accumulation of advanced glycation end products (AGEs) causes metabolic dysfunction and neuronal cell damage. Methylglyoxal (MG) is a major glycating agent that reacts with basic residues present in proteins and promotes the formation of AGEs. Sciadopitysin, a type of biflavonoid, exerts protective effects against neuronal cell damage; however, the underlying mechanisms have not been studied. This study aimed to investigate the mechanisms underlying the protective effects of sciadopitysin against MG-mediated cytotoxicity in SK-N-MC neuroblastoma cells. Our results demonstrated that pretreatment of SK-N-MC cells with sciadopitysin improved the cell viability that was inhibited by MG and inhibited the apoptosis induced by MG. Sciadopitysin attenuated intracellular Ca2+ , NOX4 levels, oxidative stress, and MG-protein adduct levels, and increased nuclear Nrf2 and glyoxalase 1 levels in the presence of MG. These results suggest that sciadopitysin exerts neuroprotective effects against MG-induced death of human SK-N-MC cells via its antioxidative action. This study highlights sciadopitysin as a promising candidate for antioxidant therapy and designing natural drugs against AGE-induced neurodegenerative disorders.

Collecting Duct-Specific CR6-Interacting Factor-1-Deletion Aggravates Renal Inflammation and Fibrosis Induced by Unilateral Ureteral Obstruction.

Although inflammation and fibrosis, which are key mechanisms of chronic kidney disease, are associated with mitochondrial damage, little is known about the effects of mitochondrial damage on the collecting duct in renal inflammation and fibrosis. To generate collecting duct-specific mitochondrial injury mouse models, CR6-interacting factor-1 (CRIF1) flox/flox mice were bred with Hoxb7-Cre mice. We evaluated the phenotype of these mice. To evaluate the effects on unilateral ureteral obstruction (UUO)-induced renal injury, we divided the mice into the following four groups: a CRIF1flox/flox (wild-type (WT)) group, a CRIF1flox/flox-Hob7 Cre (CRIF1-KO) group, a WT-UUO group, and a CRIF1-KO UUO group. We evaluated the blood and urine chemistries, inflammatory and fibrosis markers, light microscopy, and electron microscopy of the kidneys. The inhibition of Crif1 mRNA in mIMCD cells reduced oxygen consumption and membrane potential. No significant differences in blood and urine chemistries were observed between WT and CRIF1-KO mice. In UUO mice, monocyte chemoattractant protein-1 and osteopontin expression, number of F4/80 positive cells, transforming growth factor-ß and α-smooth muscle actin staining, and Masson's trichrome staining were significantly higher in the kidneys of CRIF1-KO mice compared with the kidneys of WT mice. In sham mice, urinary 8-hydroxydeoxyguanosine (8-OHDG) was higher in CRIF1-KO mice than in WT mice. Moreover, CRIF1-KO sham mice had increased 8-OHDG-positive cell recruitment compared with WT-sham mice. CRIF1-KO-UUO kidneys had increased recruitment of 8-OHDG-positive cells compared with WT-UUO kidneys. In conclusion, collecting duct-specific mitochondrial injury increased oxidative stress. Oxidative stress associated with mitochondrial damage may aggravate UUO-induced renal injury.

Spironolactone Attenuates Methylglyoxal-induced Cellular Dysfunction in MC3T3-E1 Osteoblastic Cells.

BACKGROUND: Methylglyoxal (MG) is associated with the pathogenesis of age- and diabetes-related complications. Spironolactone is a competitive antagonist of aldosterone that is widely employed in the treatment of hypertension and heart failure. This study examined the effects of spironolactone on MG-induced cellular dysfunction in MC3T3-E1 osteoblastic cells. METHODS: MC3T3-E1 cells were treated with spironolactone in the presence of MG. The mitochondrial function, bone formation activity, oxidative damage, inflammatory cytokines, glyoxalase I activity, and glutathione (GSH) were measured. RESULTS: Pretreatment of MC3T3-E1 osteoblastic cells with spironolactone prevented MG-induced cell death, and improved bone formation activity. Spironolactone reduced MG-induced endoplasmic reticulum stress, production of intracellular reactive oxygen species, mitochondrial superoxides, cardiolipin peroxidation, and inflammatory cytokines. Pretreatment with spironolactone also increased the level of reduced GSH and the activity of glyoxalase I. MG induced mitochondrial dysfunction, but markers of mitochondrial biogenesis such as mitochondrial membrane potential, adenosine triphosphate, proliferator-activated receptor gamma coactivator 1α, and nitric oxide were significantly improved by treatment of spironolactone. CONCLUSION: Spironolactone could prevent MG-induced cytotoxicity in MC3T3-E1 osteoblastic cells by reduction of oxidative stress. The oxidative stress reduction was explained by spironolactone's inhibition of advanced glycation end-product formation, restoring mitochondrial dysfunction, and anti-inflammatory effect.

Mitochondrial Dysfunction in Podocytes Caused by CRIF1 Deficiency Leads to Progressive Albuminuria and Glomerular Sclerosis in Mice.

Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.

Oleuropein attenuates the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-perturbing effects on pancreatic ß-cells.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine disrupting compound and persistent organic pollutant that has been associated with diabetes in several epidemiological studies. Oleuropein, a major phenolic compound in olive fruit, is a superior antioxidant and radical scavenger. This study aimed to examine the effects of oleuropein against TCDD-induced stress response in a pancreatic beta cell line, INS-1 cells. Cells were pre-incubated with various concentrations of oleuropein and then stimulated with TCDD (10 nM) for 48 hrs. When treated with TCDD, INS-1 cells produced robust amounts of prostaglandin E2 (PGE2) compared to the untreated control, and this increase was inhibited by oleuropein treatment. TCDD increased Ca2+-independent phospholipase A2 (iPLA2ß) level, but had no effect on Group 10 secretory phospholipase A2 (PLA2G10) level, while oleuropein deceased the levels of iPLA2ß and PLA2G10 in the presence of TCDD. Cyclooxygenase-1 (COX-1) was significantly increased by TCDD treatment and attenuated with oleuropein pretreatment. Oleuropein decreased TCDD-mediated production of JNK, TNF-α, and ROS. In addition, oleuropein increased Akt and GLUT2 levels suppressed by TCDD in INS-1 cells. Thus, the results suggest that oleuropein prevents pancreatic beta cell impairment by TCDD.

Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer.

Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8+ T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8+ T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.

Prognostic value of changes in serum carcinoembryonic antigen levels for preoperative chemoradiotherapy response in locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is a standard treatment modality for locally advanced rectal cancer. However, CRT alone cannot improve overall survival. Approximately 20% of patients with CRT-resistant tumors show disease progression. Therefore, predictive factors for treatment response are needed to identify patients who will benefit from CRT. We theorized that the prognosis may vary if patients are classified according to pre- to post-CRT changes in carcinoembryonic antigen (CEA) levels. AIM: To identify patients with locally advanced rectal cancer for preoperative chemoradiotherapy based on carcinoembryonic antigen levels. METHODS: We retrospectively included locally advanced rectal cancer patients who underwent preoperative CRT and curative resection between 2011 and 2017. Patients were assigned to groups A, B, and C based on pre- and post-CRT serum CEA levels: Both > 5; pre > 5 and post ≤ 5; and both ≤ 5 ng/mL, respectively. We compared the response to CRT based on changes in serum CEA levels. Receiver operating characteristic curve analysis was performed to determine optimal cutoff for neutrophil-lymphocyte ratio and platelet-lymphocyte ratio. Multivariate logistic regression analysis was used to evaluate the prognostic factors for pathologic complete response (pCR)/good response. RESULTS: The cohort comprised 145 patients; of them, 27, 43, and 65 belonged to groups A, B, and C, respectively, according to changes in serum CEA levels before and after CRT. Pre- (P < 0.001) and post-CRT (P < 0.001) CEA levels and the ratio of down-staging (P = 0.013) were higher in Groups B and C than in Group A. The ratio of pathologic tumor regression grade 0/1 significantly differed among the groups (P = 0.003). Group C had the highest number of patients showing pCR (P < 0.001). Most patients with pCR showed pre- and post-CRT CEA levels < 5 ng/mL (P < 0.001, P = 0.008). Pre- and post-CRT CEA levels were important risk factors for pCR (OR = 18.71; 95%CI: 4.62-129.51, P < 0.001) and good response (OR = 5.07; 95%CI: 1.92-14.83, P = 0.002), respectively. Pre-CRT neutrophil-lymphocyte ratio and post-CRT T ≥ 3 stage were also prognostic factors for pCR or good response. CONCLUSION: Pre- and post-CRT CEA levels, as well as change in CEA levels, were prognostic markers for treatment response to CRT and may facilitate treatment individualization for rectal cancer.

Clinical Significance of Tumor and Immune Cell PD-L1 Expression in Gastric Adenocarcinoma.

BACKGROUND/AIM: The prognostic relevance of programmed cell death ligand-1 (PD-L1) protein expression in gastric cancer (GC) remains controversial. The aims of the present study were to determine the correlations between tumor cell (TC) and immune cell (IC) PD-L1 protein levels with prognosis, and to determine the correlation between PD-L1 expression and different molecular GC subtypes. MATERIALS AND METHODS: TC and IC PD-L1 protein levels were measured in 286 GC patients. The patients were classified according to the Cancer Genome Atlas and Asian Cancer Research Group guidelines using immunohistochemistry and in situ hybridization. RESULTS: TC and IC PD-L1 protein levels were positively correlated with patient survival. TC PD-L1 expression was negatively correlated with tumor grade. TC and IC PD-L1 expression was associated with improved prognosis in Epstein-Barr virus negative (EBV-), microsatellite instability (MSI) rather than microsatellite stability (MSS) subgroup GC patients. CONCLUSION: PD-L1 protein expression in TCs and ICs can be used as a prognostic indicator for GC patients, particularly in the EBV-, MSI, and MSS subgroups.

Diagnostic significance of dual immunocytochemical staining of p53/cytokeratin20 on liquid-based urine cytology to detect urothelial carcinoma.

BACKGROUND: Urine cytology is a noninvasive and inexpensive method; however, it is limited in low sensitivity for detecting and monitoring urothelial carcinoma (UC). To overcome limitation of cytology, several tests using urine samples have been attempted that immunocytochemical staining is an inexpensive and easy to perform ancillary technique. Dual immunocytochemical staining for p53 and cytokeratin 20 (CK20) is assessed in liquid-based urine cytology slides. MATERIALS AND METHODS: Liquid-based urine cytology samples collected between 2008 and 2013 and matched follow-up biopsy samples of high-grade UC (HGUC) (n = 44) and low-grade UC (LGUC) (n = 14) were analyzed. RESULTS: Urine cytology showing atypical cells was subjected to dual-color immunostaining for p53 and CK20. The sensitivity of urine cytology combined with p53 and CK20 immunostaining was 77.3% in HGUC and 52.9% in LGUC. Of 20 cases diagnosed with atypia by urine cytology, 13 (65%) were positive for p53 or CK20. Dual immunocytochemical staining for p53/CK20 improved the diagnostic accuracy of urine cytology. CONCLUSIONS: The present results indicate that cytomorphology combined with p53/CK20 immunostaining is useful for the detection of HGUC and LGUC.

Orientin reduces the inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin signaling pathway in murine 3T3-L1 adipocytes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) accumulates in human body, probably influencing adipocyte differentiation and causing various toxic effects, including wasting syndrome. Recently, orientin, a phenolic compound abundant in natural health products, has been shown to have antioxidant properties. We investigated the protective effects of orientin against TCDD-induced adipocyte dysfunction and its underlying mechanisms. In this study, orientin suppressed TCDD-induced loss of lipid accumulation. Orientin inhibited TCDD-driven decreases in the levels of peroxisome proliferator-activated receptor γ and adiponectin. Orientin also reduced TCDD-induced prostaglandin E2, and cytosolic phospholipase A2α levels, and increased TCDD-inhibited peroxisome proliferator-activated receptor gamma coactivator 1-alpha levels in 3T3-L1 adipocytes. TCDD reduced the levels of insulin receptor substrate 1 and glucose transporter 4, and decreased insulin-stimulated glucose uptake activity; however, orientin diminished these TCDD-induced effects. These results suggest that orientin may have beneficial effects on the prevention of TCDD-induced wasting syndrome and type II diabetes mellitus accompanied by insulin resistance.

Complement Component C4d Deposition in the Placenta of Preeclampsia Patients and Renal Glomeruli in 1 Postpartum Renal Biopsy.

BACKGROUND: The classic disorder of placental malperfusion is preeclampsia (PE), in which the kidney is also a target organ, leading to renal dysfunction. Although the precise pathogenesis of PE is unknown, increasing evidence suggests that PE is associated with complement dysregulation. The maternal immune response to an allogenic fetus and excessive activation of the complement system may both be involved in the pathogenesis of PE. C4d deposition is considered to be evidence of antibody-mediated rejection in an allograft. This study investigated a correlation between C4d expression in the placenta and clinicopathologic features of PE patients. MATERIALS AND METHODS: Immunohistochemical staining for C4d was performed on placental tissue of PE patients (n=70) and normal pregnancy patients (n=30). Clinicopathologic features, such as maternal age and parity, placental weight, proteinuria, and histologic features of the placenta were evaluated. One PE patient who suffered from proteinuria after delivery received a renal biopsy. RESULTS: C4d expression was demonstrated in syncytiotrophoblast of chorionic villi. The expression of C4d was significantly more frequent in the placenta with PE (50%) than in the placenta lacking complications (14.3%) (P=0.001). C4d expression was significantly accompanied by increased syncytial knots in PE (P=0.045). Among PE patients, C4d expression was significantly correlated with low placental weight (P=0.001) and high proteinuria (P=0.018, Mann-Whitney U test). Renal biopsy of a PE patient after delivery also showed deposition of C4d along the glomerular capillary walls. CONCLUSIONS: C4d may play an important role in placental tissue injury and in renal complications in PE.

Tetrabromobisphenol A Promotes the Osteoclastogenesis of RAW264.7 Cells Induced by Receptor Activator of NF-kappa B Ligand In Vitro.

BACKGROUND: Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame-retardants, is a representative persistent organic pollutants group. Studies on TBBPA toxicity have been conducted using various target cells; however, few studies have investigated TBBPA toxicity in bone cells. Therefore, this study investigated the in vitro effects of TBBPA on osteoclasts, a cell type involved in bone metabolism. METHODS: RAW264.7 cells were cultured in medium containing 50 ng/mL receptor activator of nuclear factor kappa B ligand (RANKL) and varying concentrations of TBBPA. To evaluate the effects of TBBPA on the differentiation and function of osteoclasts, osteoclast-specific gene expression, tartrate-resistant acid phosphatase (TRAP) activity, bone resorbing activity, mitochondrial membrane potential (MMP) and mitochondrial superoxide were measured. RESULTS: The presence of 20 µ TBBPA significantly increased TRAP activity in RANKL-stimulated RAW264.7 cells, the bone resorbing activity of osteoclasts, and the gene expression of Akt2, nuclear factor of activated T-cells cytoplasmic 1, and chloride channel voltage-sensitive 7. However, TBBPA treatment caused no change in the expression of carbonic anhydrase II, cathepsin K, osteopetrosis-associated transmembrane protein 1, Src, extracellular signal-related kinase, GAB2, c-Fos, or matrix metalloproteinase 9. Furthermore, 20 µ TBBPA caused a significant decrease in MMP and a significant increase in mitochondrial superoxide production. CONCLUSION: This study suggests that TBBPA promotes osteoclast differentiation and activity. The mechanism of TBBPA-stimulated osteoclastogenesis might include increased expression of several genes involved in osteoclast differentiation and reactive oxygen species production.