CX3CR1 deficiency promotes resolution of hepatic ischemia-reperfusion injury by regulating homeostatic function of liver infiltrating macrophages.

Hepatic ischemia-reperfusion injury(HIRI) remains to be an unsolved risk factor that contributes to organ failure after liver surgery. Our clinical retrospective study showed that lower donor liver CX3-C chemokine receptor-1(CX3CR1) mRNA expression level were correlated with upregulated pro-resolved macrophage receptor MERTK, as well as promoted restoration efficiency of allograft injury in liver transplant. To further characterize roles of CX3CR1 in regulating resolution of HIRI, we employed murine liver partial warm ischemia-reperfusion model by Wt & Cx3cr1-/- mice and the reperfusion time was prolonged from 6 h to 4-7 days. Kupffer cells(KCs) were depleted by clodronate liposome(CL) in advance to focus on infiltrating macrophages, and repopulation kinetics were determined by FACS, IF and RNA-Seq. CX3CR1 antagonist AZD8797 was injected i.p. to interrogate potential pharmacological therapeutic strategies. In vitro primary bone marrow macrophages(BMMs) culture by LXR agonist DMHCA, as well as molecular and functional studies, were undertaken to dissect roles of CX3CR1 in modulating macrophages cytobiological development and resolutive functions. We observed that deficiency or pharmacological inhibition of CX3CR1 facilitated HIRI resolution via promoted macrophages migration in CCR1/CCR5 manner, as well as enhanced MerTK-mediated efferocytosis. Our study demonstrated the critical roles of CX3CR1 in progression of HIRI and identified it as a potential therapeutic target in clinical liver transplantation.

Platycodin D alleviates liver fibrosis and activation of hepatic stellate cells by regulating JNK/c-JUN signal pathway.

Liver fibrosis is involved in the progression of most chronic liver diseases. Even though we have made a huge progress in order to understand the pathogenesis of liver fibrosis, however, there is still a lack of productive treatments. Being a traditional Chinese medicine, Platycodin D (PD), an oleanane kind of triterpenoid saponin has been put to extensive use for treating different kinds of illnesses that include not just anti-nociceptive, but also antiviral, anti-inflammatory, and anti-cancer for thousands of years. Nonetheless, there has been no clarification made for its effects on the progression of liver fibrosis. In this manner, we carried out in vitro studies for the purpose of investigating the anti-fibrosis impact of PD. Activation of hepatic stellate cells was evaluated by means of the detection of the proliferation of HSCs and the expression of specific proteins. We discovered the fact that PD had the potential of activating HSCs. Thereafter, we detected the apoptosis and autophagy of the HSCs; as the results suggested, PD induced apoptosis and autophagy of the HSCs. It augmented the expression level of apoptotic proteins that included Bax, Cytochrome C (cyto-c), cleaved caspase3 and cleaved caspase9, in addition to the autophagy relevant proteins, for instance, LC3II, beclin1, Atg5 and Atg9. Further research was carried out for the investigation of the underlying molecular mechanism, and discovered that PD promoted the phosphorylation of JNK and c-Jun. Treating the JNK inhibitor P600125 inhibited the effect of PD, confirming the impact of PD on the regulation of JNK/c-Jun pathway. Thus, we speculated that PD alleviates liver fibrosis and activation of hepatic stellate via promoting phosphorylation of JNK and c-Jun and further altering the autophagy along with apoptosis of HSCs.

AST to ALT ratio and arterial stiffness in non-fatty liver Japanese population:a secondary analysis based on a cross-sectional study.

BACKGROUND: Previous studies have revealed that triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio (henceforth TG/HDL-C) is one of the major risk factors for cardiovascular disease, insulin resistance and metabolism syndrome. However, there are fewer investigations of the correlations between the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and brachial ankle pulse wave velocity (baPWV). This study was undertaken to investigate the relationship between the AST to ALT ratio and brachial-ankle pulse wave velocity (baPWV) in a Japanese population. METHODS: The present study was a cross-sectional study. A total of 646 Japanese men and women without fatty liver, aged 24-84 years old, received a health medical check-up programme including the results from baPWV inspection and various standardized questionnaires in a health examination centre in Japan. Main outcome measures included AST/ALT ratio, baPWV, fatty liver and postmenopausal status. Abdominal ultrasonography was used to diagnose fatty liver. A postmenopausal state was defined as beginning 1 year following the cessation of menses. RESULTS: After adjusting for potential confounders (age, sex, BMI, SBP, DBP, AST, ALT, GGT, uric acid, fasting glucose, TC, LDL, eGFR, smoking and exercise statuses, fatty liver, alcohol consumption and ABI), a non-linear relationship was detected between AST/ALT and baPWV, which had an inflection point of 5.6. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 12.7 (1.9 to 23.5) and - 16.7 (- 36.8 to 3.3), respectively. Subgroup analysis in participants with excessive alcohol consumption (more than 280 g/week) showed that AST/ALT had a negative correlation with baPWV (ß = - 30.7, 95%CI (- 53.1, - 8.4)), and the P value for the interaction was less than 0.05. CONCLUSION: The relationship between AST/ALT and baPWV is non-linear. AST/ALT was positively correlated with baPWV when AST/ALT was less than 5.6. In addition, the trend was the opposite in subjects who consumed excessive amounts of alcohol.

Cesarean Scar Pregnancy, Incidence, and Recurrence: Five-Year Experience at a Single Tertiary Care Referral Center.

OBJECTIVE: To describe the treatment and subsequent pregnancy outcomes in patients with cesarean scar pregnancies at a single institution over 5 years. METHODS: This is a case series of all cesarean scar pregnancies diagnosed from May 2013 to March 2018 at Yale-New Haven Hospital. Data were collected on each patient using electronic medical record review and included patient demographics; medical, surgical, and obstetric history; pregnancy characteristics; treatment modalities used; response to therapy; complications; and subsequent pregnancy outcomes. RESULTS: Thirty cases of cesarean scar pregnancies were diagnosed in 26 patients, including one recurrence in one patient and three recurrences in another. Forty-six percent of cesarean scar pregnancies were in Hispanic women. The median number of prior cesarean deliveries was two. Mean gestational age at the time of diagnosis was 46 days (SD±10). Fetal cardiac activity was detected in 18 cases. Three patients initially were erroneously diagnosed with a viable intrauterine pregnancy and failed medical termination. Others opted for termination through systemic methotrexate alone (n=4), systemic and local methotrexate (n=12), systemic and local methotrexate with potassium chloride injected into the gestational sac (n=3), potassium chloride injection with laparotomy and wedge resection (n=1), methotrexate with bilateral uterine artery embolization (n=2), or intrauterine balloon (n=4). Five patients who underwent expectant management or methotrexate therapy had retained products of conception and required hysteroscopy and curettage. One patient opted for hysterectomy after failed curettage. After complete resolution of cesarean scar pregnancies, there were 10 subsequent spontaneous conceptions in eight patients, including four recurrent cesarean scar pregnancies, four term pregnancies, and one spontaneous abortion. One viable normally located pregnancy is ongoing. CONCLUSION: There is a wide array of treatment modalities available for cesarean scar pregnancies. Women with a cesarean scar pregnancy are at risk for its recurrence in the future, although normal pregnancy after a cesarean scar pregnancy is also possible. Safe outcomes depend on timely diagnosis and multidisciplinary care by skilled clinicians.

Decreased Surgical Site Infection Rate in Hysterectomy: Effect of a Gynecology-Specific Bundle.

OBJECTIVE: We implemented a hysterectomy-specific surgical site infection prevention bundle after a higher-than-expected surgical site infection rate was identified at our institution. We evaluate how this bundle affected the surgical site infection rate, length of hospital stay, and 30-day postoperative readmission rate. METHODS: This is a quality improvement study featuring retrospective analysis of a prospectively implemented, multidisciplinary team-designed surgical site infection prevention bundle that consisted of chlorhexidine-impregnated preoperative wipes, standardized aseptic surgical preparation, standardized antibiotic dosing, perioperative normothermia, surgical dressing maintenance, and direct feedback to clinicians when the protocol was breached. RESULTS: There were 2,099 hysterectomies completed during the 33-month study period. There were 61 surgical site infections (4.51%) in the pre-full bundle implementation period and 14 (1.87%) in the post-full bundle implementation period; we found a sustained reduction in the proportion of patients experiencing surgical site infection during the last 8 months of the study period. After adjusting for clinical characteristics, patients who underwent surgery after full implementation were less likely to develop a surgical site infection (adjusted odds ratio [OR] 0.46, P=.01) than those undergoing surgery before full implementation. Multivariable regression analysis showed no statistically significant difference in postoperative days of hospital stay (adjusted mean ratio 0.95, P=.09) or rate of readmission for surgical site infection-specific indication (adjusted OR 2.65, P=.08) between the before and after full-bundle implementation periods. CONCLUSION: The multidisciplinary implementation of a gynecologic perioperative surgical site infection prevention bundle was associated with a significant reduction in surgical site infection rate in patients undergoing hysterectomy.

Occult Gynecologic Cancer in Women Undergoing Hysterectomy or Myomectomy for Benign Indications.

OBJECTIVE: To estimate the prevalence of corpus uteri, cervix uteri, and ovarian malignancy in women undergoing hysterectomy or myomectomy for presumed benign indications. METHODS: We conducted a secondary analysis of data from the 2014-2015 American College of Surgeons National Surgical Quality Improvement Program. Adult women undergoing hysterectomies and myomectomies without evidence for known or suspected cancer at the beginning of surgery were identified from the database. Our primary outcome measure was pathology-confirmed malignancy in the corpus uteri, cervix uteri, and ovary. We performed adjusted logistic regression analysis to examine the association of patient characteristics with the risk for malignancy. RESULTS: Our sample included 24,076 women undergoing hysterectomy and 2,368 women undergoing myomectomy. Malignancy of the corpus uteri was found in 1.44% (95% CI 1.29-1.59%) of the women undergoing hysterectomy. The prevalence varied considerably across surgical routes with the rate being 0.23% (95% CI 0.06-0.58%) in laparoscopic supracervical hysterectomy and 1.89% (95% CI 1.65-2.14%) in total laparoscopic or laparoscopic-assisted vaginal hysterectomy. Older women were significantly more likely to have preoperatively undetected malignancy of the corpus uteri (adjusted odds ratio 6.46, 95% CI 4.96-8.41 for age 55 years or older vs age 40-54 years). Additionally, 0.60% (95% CI 0.50-0.70%) and 0.19% (95% CI 0.14-0.25%) of the women undergoing hysterectomy were found to have malignancy of the cervix uteri and the ovary, respectively. Among patients undergoing myomectomy, 0.21% (95% CI 0.03-0.40%) were found to have malignancy of the corpus uteri with no occult cervical or ovarian cancer identified. CONCLUSION: Prevalence of occult corpus uteri, cervical, and ovarian malignancy was 1.44%, 0.60%, and 0.19%, respectively, among women undergoing hysterectomy and it varied by patient age and surgical route.

Inpatient Laparoscopic Hysterectomy in the United States: Trends and Factors Associated With Approach Selection.

STUDY OBJECTIVE: To examine utilization patterns of different laparoscopic approaches in inpatient hysterectomy and identify patient and hospital characteristics associated with the selection of specific laparoscopic approaches. DESIGN: Using data from the 2007 to 2012 National (Nationwide) Inpatient Sample (NIS), we identified adult women undergoing inpatient laparoscopic hysterectomy for nonobstetric indications based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Benign cases were categorized based on laparoscopic approach, classified as total laparoscopic hysterectomy (TLH), laparoscopic-assisted vaginal hysterectomy (LAVH), or laparoscopic supracervical hysterectomy (LSH). We assessed changes in the use of these approaches during 2007 to 2012, and used multinomial logistic regression to examine the association of patient and hospital characteristics with the choice of laparoscopic approach in 2012. The NIS sample weights were applied to generate nationally representative estimates. DESIGN CLASSIFICATION: Retrospective study (Canadian Task Force classification III). SETTING: Hospital inpatient care nationwide. PATIENTS: Female adult patients in the NIS database who underwent an inpatient laparoscopic hysterectomy between 2007 and 2012. INTERVENTION: Inpatient laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: Of the inpatient laparoscopic hysterectomies performed in 2012, 83.2% were for benign indications. The TLH approach accounted for 48.3% of all laparoscopic hysterectomies, followed by LAVH at 37.3% and LSH at 14.4%. Robotic assistance was reported in 45.0% of all cases and 72.3% of malignant hysterectomies. An examination of temporal trends during 2007 to 2012 demonstrates a shift in the laparoscopic approach from LAVH toward TLH, with a slight decrease in LSH. Patient race/ethnicity, income, indication for hysterectomy, and comorbid conditions, as well as hospital teaching status, urban/rural location, bed size, type of ownership, and geographic region, were significantly associated with the choice of laparoscopic approach. CONCLUSION: Benign laparoscopic hysterectomy is increasingly performed as TLH rather than LAVH. In addition to clinical factors, the selection of laparoscopic approach is influenced by patient socioeconomic and hospital characteristics.

Surgical site infections in gynecology.

IMPORTANCE: Surgical site infections (SSIs) are preventable, yet nearly 2% of all surgical cases are complicated by an SSI. Each SSI increases the cost of a postoperative hospital stay by more than $10,000. Thus, SSI prevention has become the focus of health care systems and hospitals because it is a reducible health care cost. OBJECTIVE: The objective of this review was to better understand the guidelines and recommendations related to the prevention, diagnosis, and management of SSIs. EVIDENCE ACQUISITION: This study is a thorough review of the most up-to-date peer-reviewed articles and review articles as well as guidelines and recommendations of various professional organizations including the US Centers for Disease Control and Prevention and the American College of Obstetrics and Gynecology. RESULTS: A review of the literature has identified several evidence-based recommendations that physicians should adhere to in an effort to decrease the incidence of SSIs. CONCLUSIONS AND RELEVANCE: By adhering to clinical recommendations and evidence, we can correctly prevent, diagnose, and treat SSIs. In turn, this will improve health outcomes and decrease health care-related costs, thus increasing the value of health care that we provide to patients. Furthermore, we can gain improvements in the quality measures used by hospitals and insurers.

Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated.

Tumor-associated macrophages (TAMs) may have an important role in tumor immunity. We studied the activation state of TAMs in cutaneous SCC, the second most common human cancer. CD163 was identified as a more abundant, sensitive, and accurate marker of TAMs when compared with CD68. CD163(+) TAMs produced protumoral factors, matrix metalloproteinases 9 and 11 (MMP9 and MMP11), at the gene and protein levels. Gene set enrichment analysis (GSEA) was used to evaluate M1 and M2 macrophage gene sets in the SCC genes and to identify candidate genes in order to phenotypically characterize TAMs. There was coexpression of CD163 and alternatively activated "M2" markers, CD209 and CCL18 (chemokine (C-C motif) ligand 18). There was enrichment for classically activated "M1" genes in SCC, which was confirmed in situ by colocalization of CD163 and phosphorylated STAT1 (signal transducer and activator of transcription 1), IL-23p19, IL-12/IL-23p40, and CD127. Also, a subset of TAMs in SCC was bi-activated as CD163(+) cells expressed markers for both M1 and M2, shown by triple-label immunofluorescence. These data support heterogeneous activation states of TAMs in SCC, and suggest that a dynamic model of macrophage activation would be more useful to characterize TAMs.

Myeloid dendritic cells from human cutaneous squamous cell carcinoma are poor stimulators of T-cell proliferation.

To determine the phenotype and function of myeloid dendritic cells (DCs) from human cutaneous squamous-cell carcinoma (SCC), we studied their surface marker expression and allo-stimulatory potential ex vivo. There were abundant CD11c(+) myeloid DCs, as well as TNF and inducible nitric oxide synthase (iNOS)-producing DCs, in and around SCC tumor nests. Although myeloid DCs from SCC, adjacent non-tumor-bearing skin, and normal skin, were phenotypically similar by flow cytometry, and there was a pronounced genomic signature of mature DCs in SCC, they showed different T-cell stimulatory potential in an allogeneic mixed leukocyte reaction. Myeloid DCs from SCC were less potent stimulators of allogeneic T-cell proliferation than DCs from non-tumor-bearing skin. Culture with a DC-maturing cytokine cocktail (IL-1beta, IL-6, TNF-alpha, and PGE(2)) enhanced stimulatory potential in DCs from non-tumor-bearing skin, whereas SCC-associated DCs remained poor stimulators of T-cell proliferation. The microenvironment associated with SCC showed expression of TGF-beta, IL-10, and VEGF-A, factors capable of suppressing the DC function. These findings indicate that CD11c(+)/HLA-DR(hi) DCs from SCC are mature, but are not potent stimulators of T-cell proliferation compared with phenotypically similar DCs isolated from non-tumor-bearing skin. Identification of mechanisms responsible for suppression of tumor-associated DCs may provide insight into the evasion of immunosurveillance by SCC.

Fertility sparing therapy for ovarian cancer has inherent risks and benefits.

INTRODUCTION: Fertility sparing therapy for epithelial ovarian cancer has been suggested for well-selected patients with early stage disease. The overall recurrence rate of 10% and 5-year disease free survival greater than 90% is similar in conservative and traditional surgical management of epithelial ovarian cancer. Thus, conservative approaches may be considered in young women diagnosed with FIGO stage I cancer who wish to preserve reproductive function. Subsequent use of assisted reproductive technologies (ART) may facilitate production of biologic offspring in these cancer survivors. However, each candidate requires unique consideration by subspecialists to avoid potentially fatal management errors. CASE REPORT: We present two cases in which fertility sparing therapy for early stage epithelial ovarian cancer was considered. The first case delineates the comprehensive work-up required to identify candidates for this therapy, while the second case illustrates the successful application of a fertility sparing approach. DISCUSSION: The conservative management of early epithelial ovarian cancer and use of ART to obtain offspring are reviewed.