Hospital surgical volume-outcome relationship in caesarean hysterectomy for placenta accreta spectrum.

OBJECTIVE: To examine the association between hospital surgical volume of caesarean hysterectomy and surgical morbidity in women with placenta accreta spectrum (PAS). DESIGN: Population-based retrospective cohort study. SETTING: National Inpatient Sample, January 2016 to December 2018. POPULATION: Six thousand and ten women with PAS who underwent caesarean hysterectomy in 738 centres. METHODS: (1) Comprehensive modelling for relative hospital surgical volume cut-point selection, (2) multinomial regression analysis for characterising hospital surgical volume, and (3) binary logistic regression analysis to examine the volume-outcome relationship. MAIN OUTCOME MEASURES: Surgical morbidity (haemorrhage, coagulopathy, shock, urinary tract injury, and death). RESULTS: The majority of centres had five surgeries over the 3-year period (468 centres, 63.4%) and were grouped as the low-volume group. Surgical morbidity decreased after a relative hospital surgical volume of 25 cases (24 centres, 3.3%) was reached, grouped as the high-volume group. The remaining centres were grouped as the mid-volume group (246 centres, 33.3%). In multivariable analysis, women in the high-volume group were more likely to be Black, have lower median household income, medical comorbidity, previous caesarean delivery, placenta praevia or placenta percreta, and to have undergone surgeries at large urban teaching hospitals compared with those in the low-volume group (all, P < 0.05). After controlling for patient demographics, hospital characteristics and pregnancy factors, performance of caesarean hysterectomy at high-volume centres was associated with a 22% decreased risk of surgical complications compared with surgery at the low-volume centres (adjusted odds ratio 0.78, 95% CI 0.64-0.94). CONCLUSION: Caesarean hysterectomy for PAS is a rare surgical procedure. Higher hospital surgical volume may be associated with improved surgical outcome in PAS. TWEETABLE ABSTRACT: Higher hospital caesarean hysterectomy volume may be associated with improved surgical outcome in PAS.

Conservative surgery for ovarian torsion in young women: perioperative complications and national trends.

OBJECTIVE: To analyse populational trends and perioperative complications following conservative surgery versus oophorectomy in women <50 years of age with ovarian torsion. DESIGN: Population-based retrospective observational study. SETTING: Nationwide Inpatient Sample in the USA (2001-2015). POPULATION: In all, 89 177 ovarian torsions including 20 597 (23.1%) conservative surgeries and 68 580 (76.9%) oophorectomies. METHODS: (1) Trend analysis to assess utilisation of conservative surgery over time, (2) multivariable binary logistic regression to identify independent factors associated with conservative surgery and (3) inverse probability of treatment weighting with a generalised estimating equation to analyze perioperative complications. MAIN OUTCOME MEASURES: Trends, characteristics and complications related to conservative surgery. RESULTS: Performance of conservative surgery increased from 18.9 to 25.1% between 2001 and 2015 (32.8% relative increase, P = 0.001) but decreased steadily after age 15, and sharply declined after age 35 (P < 0.001). On multivariable analysis, younger age exhibited the largest effect size for conservative surgery among the independent factors (adjusted odds ratios 3.39-7.96, P < 0.001). In the weighted model, conservative surgery was associated with an approximately 30% decreased risk of perioperative complications overall (10.0% versus 13.6%, odds ratio 0.73, 95% confidence interval 0.62-0.85, P < 0.001) and was not associated with venous thromboembolism (0.2 versus 0.3%, P = 0.457) or sepsis (0.4 versus 0.3%, P = 0.638). CONCLUSION: There has been an increasing utilisation of conservative surgery for ovarian torsion in the USA in recent years. Our study suggests that conservative surgery for ovarian torsion may not be associated with increased perioperative complications. TWEETABLE ABSTRACT: Conservative surgery for ovarian torsion may not be associated with increased perioperative complications.

Outcomes in two patients with vocal fold palsy who underwent revision arytenoid adduction surgery.

OBJECTIVE: This study investigated the position of adduction thread attachment, pulling direction and fixation position in revision arytenoid adduction surgery performed in two patients with left vocal fold palsy in whom satisfactory speech improvement had not been obtained by arytenoid adduction and type 1 thyroplasty. METHODS: Revision arytenoid adduction surgery was performed with the vocal fold in the midline position in both cases. A type 1 thyroplasty procedure was subsequently added in one case because of worsened quality of speech following arytenoid adduction. RESULTS AND CONCLUSION: Although the arytenoid adduction procedure is conceptually well established, there is still room for debate concerning the actual surgical procedures used. The technique described in this report is effective, suggesting that it is worthy of recognition as an index procedure.

Comparison of lateral microsurgical preauricular and anterior endoscopic approaches to the jugular foramen.

INTRODUCTION: This project compares access to the anterolateral part of the jugular foramen provided by the lateral microsurgical preauricular and the anterior endoscopic approaches, and defines the important landmarks involved in each approach. STUDY DESIGN: Cadaveric study. RESULTS: The endoscopic transnasal/transmaxillary transpterygoid corridor provides a less invasive route for selected lesions in the jugular foramen than the traditional open route through the preauricular subtemporal infratemporal fossa approach. However, the anterior endoscopic approach provides a smaller channel to the jugular foramen than the preauricular approach. CONCLUSIONS: The anterior endoscopic approach to the anterolateral part of the jugular foramen is a useful alternative to the lateral microsurgical preauricular approach in carefully selected cases. The vaginal process of the tympanic part of the temporal bone provides a valuable landmark to aid in accessing the jugular foramen in both procedures and can be drilled to open the foramen in the preauricular approach.

Trauma-Related Critical Care.

BACKGROUND: Post-trauma resuscitation has evolved based on civilian and wartime experiences over the last decade. Similarly, data from large multicenter randomized trials have changed the management of critically ill trauma patients in the intensive care unit. METHODS: This is a review of the literature focusing on areas relevant to the management of trauma patients in the intensive care unit. RESULTS: The following topics are included: (1) ventilator management, (2) trauma sepsis, (3) use of vasopressors in hemorrhage, (4) glucose control, (5) nutrition, and (6) hemodynamic monitoring. CONCLUSION: This review demonstrated the most recent data of trauma-related critical care. Further studies will be needed to settle growing controversies in the management of critically injured patients.

Androgen receptor-mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters.

The androgen receptor (AR) has a critical role in promoting androgen-dependent and -independent apoptosis in testicular cells. However, the molecular mechanisms that underlie the ligand-independent apoptosis, including the activity of AR in testicular stem cells, are not completely understood. In the present study, we generated induced pluripotent stem cells (iPSCs) from bovine testicular cells by electroporation of octamer-binding transcription factor 4 (OCT4). The cells were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4, which maintained and stabilized the expression of stemness genes and pluripotency. The iPSCs were used to assess the apoptosis activity following exposure to phthalate esters, including di (2-ethyhexyl) phthalates, di (n-butyl) phthalate, and butyl benzyl phthalate. Phthalate esters significantly reduced the expression of AR in iPSCs and induced a higher ratio of BAX/BCL-2, thereby favoring apoptosis. Phthalate esters also increased the expression of cyclin-dependent kinase inhibitor 1 (p21(Cip1)) in a p53-dependent manner and enhanced the transcriptional activity of p53. The forced expression of AR and knockdown of p21(Cip1) led to the rescue of the phthalate-mediated apoptosis. Overall, this study suggests that testicular iPSCs are a useful system for screening the toxicity of environmental disruptors and examining their effect on the maintenance of stemness and pluripotency, as well as for identifying the iPSC signaling pathway(s) that are deregulated by these chemicals.

Prolonged recurrence-free survival following OK432-stimulated dendritic cell transfer into hepatocellular carcinoma during transarterial embolization.

Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0·1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0·046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer.

Minimally cultured bone marrow mesenchymal stem cells ameliorate fibrotic lung injury.

Clinical use of bone marrow mesenchymal stem cells (BMMSCs) holds great promise for regenerative medicine in intractable lung diseases, such as lung fibrosis or acute respiratory distress syndrome. However, a severe obstacle to the clinical application of BMMSC transplantation is the time-consuming, laborious processes required for cell culture. In order to evaluate the clinical applicability of BMMSC transplantation, we tested whether engraftment of minimally cultured BMMSCs ameliorates progressive fibrotic lung injury. Differences between murine BMMSCs cultured for 2 h (2-h adherent BMMSCs) and conventionally (9-day) cultured BMMSCs were examined in vitro. The effects of grafting either type of BMMSCs on fibrotic lung injury were then assessed by transfer experiments in a murine bleomycin-induced lung fibrosis model, in which donor cells were administered 3 days after challenge. 2-h adherent BMMSCs were smaller, less granular, possessed higher proliferative capacity and expressed higher levels of several stem cell markers and chemokine receptors than 9-day cultured BMMSCs, but lower type I procollagen, alpha-smooth muscle actin, tumour necrosis factor-beta and oncogenic transcription factor c-Myc, suggesting that they may be advantageous for cell-based therapy compared with 9-day cultured BMMSCs. Grafting 2-h adherent BMMSCs ameliorated inflammatory and fibrotic lung disorders, and reduced mortality equally well or better than 9-day cultured BMMSCs. Minimally cultured BMMSCs can substitute for conventionally cultured BMMSCs and will be a promising cell source for the treatment of acute fibrotic lung injury.

5-fluorouracil-induced histopathological changes in the central nervous system of rat fetuses.

5-Fluorouracil (5-FU), a thymidylate synthesis inhibitor, has been well known to induce developmental anomalies in the craniofacial tissues and limb buds. Recently it was reported that microencephaly was also induced in rat neonates after 5-Fu-treatement in late phase of pregnancy (Kumar et al., 2006). In this study, pregnant rats were treated with 5-Fu (15, 30 or 50 mg/kg) on day 13 of gestation, and their fetuses were examined for histopathological changes, especially in the fetal central nervous system (CNS) at 12, 24 and 48 hours after treatment (HAT). At 12 HAT, an enhancement of pyknosis of neuronal progenitor cells and subsequent loss of dead cells were detected in the CNS in a dose-dependent manner. The severity of such histopathological changes in the CNS was most prominent in the telencephalon (middle and dorsal layers of the ventricular zone) and spinal cord (dorsal area). Pyknotic cells decreased towards 48 HAT in the brain while they increased towards 48 HAT in the spinal cord. Almost all of the nuclei of pyknotic cells were positively stained by TUNEL method and showed characteristics of apoptotic cells under electron microscopy. Therefore, these pyknotic cells were considered to be apoptotic ones. Enhanced apoptosis and reduced mitosis in neuronal progenitor cells in the telencephalon seem to be responsible for the later induction of microencephaly reported by Kumar et al. (2006).

A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients.

Chemokines and their receptors are key factors in the onset and progression of AIDS. Among them, accumulating evidence strongly indicates the involvement of IL-8 and its receptors, CXCR1 and CXCR2, in AIDS-related conditions. Through extensive investigation of genetic variations of the human CXCR1-CXCR2 locus, we identified a haplotype of the CXCR1 gene (CXCR1-Ha) carrying two nonsynonymous single nucleotide polymorphisms, CXCR1_300 (Met to Arg) in the N terminus extracellular domain and CXCR1_142 (Arg to Cys) in the C terminus intracellular domain. Transfection experiments with CXCR1 cDNAs corresponding to the CXCR1-Ha and the alternative CXCR1-HA haplotype showed reduced expression of CD4 and CXCR4 in CXCR1-Ha cells in human osteosarcoma cells as well as in Jurkat and CEM human T lymphocytes. Furthermore, the efficiency of X4-tropic HIV-1(NL4-3) infection was significantly lower in CXCR1-Ha cells than in CXCR1-HA cells. The results were further confirmed by a series of experiments using six HIV-1 clinical isolates from AIDS patients. A genetic association study was performed by using an HIV-1(+) patient cohort consisting of two subpopulations of AIDS with extreme phenotypes of rapid and slow progression of the disease. The frequency of the CXCR1-Ha allele is markedly less frequent in patients with rapid disease onset than those with slow progression (P = 0.0003). These results provide strong evidence of a protective role of the CXCR1-Ha allele on disease progression in AIDS, probably acting through modulation of CD4 and CXCR4 expression.

Combined therapy of transcatheter hepatic arterial embolization with intratumoral dendritic cell infusion for hepatocellular carcinoma: clinical safety.

The curative treatments for hepatocellular carcinoma (HCC), including surgical resection and radiofrequency ablation (RFA), do not prevent tumour recurrence effectively. Dendritic cell (DC)-based immunotherapies are believed to contribute to the eradication of the residual and recurrent tumour cells. The current study was designed to assess the safety and bioactivity of DC infusion into tumour tissues following transcatheter hepatic arterial embolization (TAE) for patients with cirrhosis and HCC. Peripheral blood mononuclear cells (PBMCs) were differentiated into phenotypically confirmed DCs. Ten patients were administered autologous DCs through an arterial catheter during TAE treatment. Shortly thereafter, some HCC nodules were treated additionally to achieve the curative local therapeutic effects. There was no clinical or serological evidence of adverse events, including hepatic failure or autoimmune responses in any patients, in addition to those due to TAE. Following the infusion of (111)Indium-labelled DCs, DCs were detectable inside and around the HCC nodules for up to 17 days, and were associated with lymphocyte and monocyte infiltration. Interestingly, T lymphocyte responses were induced against peptides derived from the tumour antigens, Her-2/neu, MRP3, hTERT and AFP, 4 weeks after the infusion in some patients. The cumulative survival rates were not significantly changed by this strategy. These results demonstrate that transcatheter arterial DC infusion into tumour tissues following TAE treatment is feasible and safe for patients with cirrhosis and HCC. Furthermore, the antigen-non-specific, immature DC infusion may induce immune responses to unprimed tumour antigens, providing a plausible strategy to enhance tumour immunity.

Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that maintains the glomerular and peritubular capillary (PTC) network in the kidney. The soluble form of the VEGF receptor-1 (soluble fms-like tyrosine kinase 1 (sFlt-1)) is known to regulate VEGF activity by binding VEGF in the circulation. We hypothesized that VEGF may be beneficial for maintaining glomerular filtration barrier and vascular network in rats with progressive glomerulonephritis (GN). For blockade of VEGF activity in vivo, rats were transfected twice with plasmid DNA encoding the murine sFlt-1 gene into femoral muscle 3 days before and 2 weeks after the induction of antiglomerular basement membrane antibody-induced GN. Inhibition of VEGF with sFlt-1 resulted in massive urinary protein excretion, concomitantly with downregulated expression of nephrin in nephritic rats. Further, blockade of VEGF induced mild proteinuria in normal rats. Administration of sFlt-1 affected neither the infiltration of macrophages nor crescentic formation. In contrast, treatment of sFlt-1 accelerated the progression of glomerulosclerosis and interstitial fibrosis accompanied with renal dysfunction and PTC loss at day 56. VEGF may play a role in maintaining the podocyte function as well as renal vasculature, thereby protecting glomeruli and interstitium from progressive renal insults.

Overexpression of IL-8 in the cornea induces ulcer formation in the SCID mouse.

AIMS: Although interleukin 8 (IL-8) is not produced in the normal cornea, it has been detected there in several pathological conditions. In this study, the direct effects of IL-8 overexpression on the cornea was examined. METHODS: The corneal surface of severe combined immunodeficiency mice was infected by the adenovirus vector encoding human IL-8 (IL-8/Ad5) and clinical and pathological changes were observed at various time points. RESULTS: Clinically, marked angiogenesis and ulcer formation in the cornea were observed by 12 hours and 24 hours, respectively. Histologically, prominent angiogenesis was observed in the corneal stroma at 12 hours. Cleft formation between the corneal epithelium and stroma, and neutrophil infiltration into the corneal stroma were seen at 16 hours. By 24 hours after the infection with IL-8/Ad5, a shallow ulcer was formed in the cornea. In contrast, infection with the control adenovirus carrying the beta galactosidase gene (LacZ) showed neither corneal ulceration nor neutrophil infiltration. Immunohistochemical analysis showed that infection with IL-8/Ad5 resulted in the production of IL-8 by corneal and conjunctival stromal cells. CONCLUSION: Our results indicate that IL-8 overexpression in corneal tissue causes ulcer formation in the cornea through chemoattraction of neutrophils, suggesting the aetiological role of IL-8 in some types of corneal ulcers.

CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis.

Pulmonary fibrosis is caused by various known and unknown aetiologies, but the key pathogenic mechanisms are still ill-defined. Chemokines are a large family of chemotactic cytokines that play pivotal roles in various inflammatory diseases. In the present study, the roles of chemokines in a rat model of radiation pneumonitis/ pulmonary fibrosis were examined. Accumulation of inflammatory cells and pneumonitis were observed on day 28, and diffuse alveolar wall thickening with extensive fibrosis was observed on day 56. In addition to the previously reported CCL2 (macrophage chemoattractant protein-1) induction, selective upregulation of CCL22 (macrophage-derived chemokine) and CCL17 (thymus and activation-regulated chemokine) were demonstrated for the first time in the irradiated lung tissues. Immunohistochemically, it was demonstrated that CCL22 and CCL17 were localised primarily to alveolar macrophages, whereas their receptor CC chemokine receptor 4 (CCR4) was detected on alveolar lymphocytes and macrophages. On further analysis of bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and sarcoidosis, elevated levels of CCL22, but not of CCL17, were observed in the idiopathic pulmonary fibrosis patients. Since these two chemokines play pivotal roles in various type-2 T-helper cell-dominant diseases, it was speculated that CCL22, and probably CCL17, are involved in the pathophysiology of radiation pneumonitis/pulmonary fibrosis and idiopathic pulmonary fibrosis through the recruitment of CC chemokine receptor 4-positive type-2 T-helper cells and alveolar macrophages.

Circulating lymphocyte subsets linked to intracellular cytokine profiles in normal humans.

To determine whether there is an association between intracellular cytokine profiles and the expression of surface antigens, we performed a simultaneous flow cytometric analysis of these laboratory parameters in 11 healthy volunteers. Peripheral blood lymphocytes were double-stained for CD4 or CD8, as well as CD11a, CD25, CD26, CD29 and CD45RA or the chemokine receptors CCR3, CCR4, CCR5 or CXCR3. Portions of the cell samples were cultured for 4 h in the presence of 1 microm monensin and 20 microg/ml brefeldin A with or without stimulation by phorbol myristate acetate plus ionomycin for the detection of intracellular interferon-gamma (IFN-gamma), interleukin-2 (IL-2), tumour necrosis factor (TNF)-alpha, and IL-4. As a result, CD4+CD29high helper inducer T cells were closely associated with IFN-gamma and TNF-alpha producing CD4+ cells, while CD4+CXCR3+ cells showed a negative correlation with IL-4-producing cells, suggesting that both of these CD4+ subsets consist mainly of Th1 cells. In contrast, CD4+CD45RA+ cells were correlated inversely with IFN-gamma and TNF-alpha-producing cells, and CD8+CD11ahigh killer effector and total CCR5+ cells showed an inverse correlation with IL-2 producing cells, suggesting an immunoregulatory role for these three subsets in non-pathological conditions. Therefore, monitoring of lymphocyte subsets that express functional surface antigens could provide additional information concerning immune deviation, as assessed by the production of Th1/Th2 type cytokines. Further, this type of combined study may provide clues for the pathogenesis of immune-mediated disorders.

CCR4 is an up-regulated chemokine receptor of peripheral blood memory CD4+ T cells in Crohn's disease.

Several chemokine receptors are expressed selectively on the surface of T cells depending on their polarization. The aim of this study was to characterize chemokine receptor expression in peripheral blood memory T cells in Crohn's disease (CD) and ulcerative colitis (UC), and to correlate the expression with disease activity. Peripheral blood mononuclear cells (PBMCs) were obtained from 24 patients with CD, 30 patients with UC, 24 normal controls and 10 disease controls. PBMCs were stained by anti-CCR3, CCR4, CCR5, CXCR3, CD4, CD8, CD45RO and beta 7 integrin, and the expression of the chemokine receptors were determined by flow cytometry. CCR4 expression on memory T cells was significantly lower in UC than in CD or normal controls, and that of memory CD4+ T and beta 7(high) memory CD4+ T cells was significantly higher in CD than in UC or normal controls. CCR4 expression on memory CD4+ T cells exhibited significant positive correlation with disease activity in CD, and this decreased significantly after treatment. Such a decrease was not found in the disease controls. CCR5 and CXCR3 expression on memory CD8+ T cells was significantly lower in CD than in normal controls. CXCR3 expression on beta 7(high) memory CD4+ T and CXCR3 expression on memory CD8+ T cells were lower in UC than in normal controls. These findings suggest that in peripheral blood memory T cells, chemokine receptor expression is different between CD and UC. Enhancement of CCR4 and suppression of CCR5 and CXCR3 seem to be the characteristic chemokine receptor profile in peripheral blood memory T cells of CD.

Involvement of p38 mitogen-activated protein kinase followed by chemokine expression in crescentic glomerulonephritis.

p38 Mitogen-activated protein kinase (MAPK) is involved in the production and signal transduction of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and chemokines in vitro. However, the crucial role of p38 MAPK in the inflammatory processes of crescentic glomerulonephritis in vivo remains to be investigated. We showed a dramatic decrease in IL-1beta-induced phosphorylation of p38 MAPK, not extracellular signal-regulated kinases 1/2 or jun NH2-terminal kinase, in rat cultured mesangial cells by FR167653. We explored the effects of FR167653 as a specific inhibitor of p38 MAPK on renal injury and subsequent renal expression of chemokines in a progressive experimental crescentic glomerulonephritis model in Wistar-Kyoto rats. Rats developed crescentic glomerulonephritis leading to glomerulosclerosis and interstitial fibrosis by 56 days after the administration of nephrotoxic sera. The number of phosphorylated p38 MAPK-positive cells, detected mainly in crescents, correlated well with the percentage of crescents and number of ED-1-positive cells. Phosphorylated p38 MAPK-positive cells were downregulated in glomeruli in rats with the daily subcutaneous administration of FR167653 for 6 days. Concomitantly, renal expression of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1/monocyte chemotactic and activating factor was markedly reduced by day 6. The severity of glomerulosclerosis and interstitial fibrosis significantly decreased by day 56, and renal function was preserved. These results suggest that p38 MAPK phosphorylation is pivotal for crescentic glomerulonephritis, followed by the subsequent expression of renal chemokines. This study provides evidence that regulation of p38 MAPK is a novel appealing therapeutic target for crescentic glomerulonephritis.