Review of endoscopic techniques in the diagnosis and management of cholangiocarcinoma

Cholangiocarcinoma is a rare malignancy of the biliary tract. Key factors in determining therapeutic options include knowledge of tumor extent, anatomy and obtaining tissue diagnosis. Endoscopically, there are three modalities available to make the diagnosis of cholangiocarcinoma. These include endoscopic retrograde cholangiopancreatography, endoscopic ultrasound with fine needle aspiration and cholangioscopy. Management of cholangiocarcinoma endoscopically is typically confined to stent placement for palliative purposes or as a bridge to surgery. In this article, we will review the endoscopic techniques available for the diagnosis and management of cholangiocarcinoma.

Abdominal compartment syndrome:Often overlooked conditions in medical intensive care units

Intra-abdominal hypertension(IAH)and abdominal compartment syndrome are well recognized entities among surgical patients.Nevertheless,a number of prospective and retrospective observational studies have shown that IAH is prevalent in about half of the critically ill patients in the medical intensive care units(ICU)and has been widely recognized as an independent risk factor for mortality.It is alarming to note that many members of the critical care team in medical ICU are not aware of the consequences of untreated IAH and the delay in making the diagnosis leads to increased morbidity and mortality.Frequently it is underdiagnosed and undertreated in this patient population.Elevated intraabdominal pressure decreases the blood flow to the kidneys and other abdominal viscera and also results in reduced cardiac output and difficulties in ventilating the patient because of increased intrathoracic pressure.When intraabdominal hypertension is not promptly recognized and treated,it leads to abdominal compartment syndrome,multiorgan dysfunction syndrome and death.Large volume fluid resuscitation is very common in medical ICU patients presenting with sepsis,shock and other inflammatory conditions like pancreatitis and it is one of the major risk factors for the development of intra-abdominal hypertension.This article presents an overview of the epidemiology,definitions,risk factors,pathophysiology and management of IAH and abdominal compartment syndrome in critically ill medical ICU patients.

Genetic and epigenetic changes associated with cholangiocarcinoma:From DNA methylation to microRNAs

Cholangiocarcinomas are malignant epithelial liver tumors arising from the intra- and extra-hepatic bile ducts. Little is known about the molecular development of this disease, and very few effective treatment options are available. Thus, prognosis is poor. Genetic and epigenetic changes play an integral role in the neoplastic transformation of human cells to their malignant counterparts. This review summarizes some of the more prevalent genetic alterations （by microRNA expression） and epigenetic changes （hypermethylation of specific gene promoters） that are thought to contribute to the carcinogenic process in cholancliocarcinoma.

Impact of chronic disease self-management programs on type 2 diabetes management in primary care

AIM: To assess the effectiveness of the Chronic Disease Self-Management Program(CDSMP) on glycated hemoglobin A1c(HbA1c) and selected self-reported measures.METHODS: We compared patients who received a diabetes self-care behavioral intervention, the CDSMP developed at the Stanford University, with controls whoreceived usual care on their HbA1c and selected self-reported measures, including diabetes self-care activities, health-related quality of life(HRQOL), pain and fatigue. The subjects were a subset of participants enrolled in a randomized controlled trial that took place at seven regional clinics of a university-affiliated integrated healthcare system of a multi-specialty group practice between January 2009 and June 2011. The primary outcome was change in HbA1c from randomization to 12 mo. Data were analyzed using multilevel statistical models and linear mixed models to provide unbiased estimates of intervention effects.RESULTS: Demographic and baseline clinical characteristics were generally comparable between the two groups. The average baseline HbA1c values in the CDSMP and control groups were 9.4% and 9.2%, respectively. Significant reductions in HbA1c were seen at 12 mo for the two groups, with adjusted changes around 0.6%(P < 0.0001), but the reductions did not differ significantly between the two groups(P = 0.885). Few significant differences were observed in participants' diabetes self-care activities. No significant differences were observed in the participants' HRQOL, pain, or fatigue measures.CONCLUSION: The CDSMP intervention may not lower HbA1c any better than good routine care in an integrated healthcare system. More research is needed to understand the benefits of self-management programs in primary care in different settings and populations.

Involvement of cholangiocyte proliferation in biliary fibrosis

Cholangiocytes are the epithelial cells that line the biliary tree.In the adult liver,they are a mitotically dormant cell population,unless ductular reaction is triggered by injury.The ability of cholangiocytes to proliferate is important in many different human pathological liver conditions that target this cell type,which are termed cholangiopathies(i.e.primary biliary cirrhosis,primary sclerosing cholangitis and biliary atresia).In our article,we provide background information on the morphological and functional heterogeneity of cholangiocytes,summarize what is currently known about their proliferative processes,and briefly describe the diseases that target these cells.In addition,we address recent findings that suggest cholangiocyte involvement in epithelial-to-mesenchymal transformation and liver fibrosis,and propose directions for future studies.

Effect of Quercetin on Formation of Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (AMD)

Purpose:Age-related macular degeneration(AMD)as a disease entity is "dry" at early stage and made up of two main components at late stage:atrophic AMD and exudative AMD.Quercetin acts as an anti-oxidant to protect retinal pigment epithelial cells(RPE)from damaged by oxidative stress,but its effect on formation of choroidal neovascularization(CNV)in AMD is unclear.The aim of this study is to investigate the effect of quercetin on the formation of CNV in AMD.Methods:The development of CNV induced by laser was detected.by fluorescein angiography(FA).Colored microsphere technique was used to determine the choroidal blood flow in ocular hypertensive rabbit eyes.In in vitro studies,HUVECs were treated with NaIO3,H2O2 and NaN3 to induce oxidative cell damages.The effect of quercetin on various oxidations-induced injuries in HUVECs was measured by MTT assay.HUVECs migration was assessed using a wound healing assay.Results:Quercetin significantly inhibited the formation of laser-induced CNV.The choroidal blood flow in rabbit eyes was significantly increased after quercetin instillation.In vitro results showed quercetin enhanced various oxidations-induced injuries in HUVECs and inhibited migration of HUVECs during wound healing.Conclusion:Quercetin inhibited the formation of CNV both in vivo and in vitro and increased choroidal blood flow.It could become a promising candidate for the treatment of AMD.

Dentin matrix protein 1 and phosphate homeostasis are critical for postnatal pulp, dentin and enamel formation

Deletion or mutation of dentin matrix protein 1 （DMP1） leads to hypophosphatemic rickets and defects within the dentin. However, it is largely unknown if this pathological change is a direct role of DMP1 or an indirect role of phosphate （Pi） or both. It has also been previously shown that Klotho-deficient mice, which displayed a high Pi level due to a failure of Pi excretion, causes mild defects in the dentinal structure. This study was to address the distinct roles of DMP1 and Pi homeostasis in cell differentiation, apoptosis and mineralization of dentin and enamel. Our working hypothesis was that a stable Pi homeostasis is critical for postnatal tooth formation, and that DMP1 has an antiapoptotic role in both amelogenesis and dentinogenesis. To test this hypothesis, Dmpl-null （Dmpl-/-）, Klotho-deficient （kl/kl）, Dmpl/Klotho-double-deficient （Dmpl-/-/kl/kl） and wild-type （WT） mice were killed at the age of 6 weeks. Combinations of X-ray, microcomputed tomography （I^CT）, scanning electron microscopy （SEM）, histology, apoptosis and immunohistochemical methods were used for characterization of dentin, enamel and pulp structures in these mutant mice. Our results showed that Dmpl-/- （a low Pi level） or kl/kl（a high Pi level） mice displayed mild dentin defects such as thin dentin and a reduction of dentin tubules. Neither deficient mouse line exhibited any apparent changes in enamel or pulp structure. However, the double-deficient mice （a high Pi level） displayed severe defects in dentin and enamel structures, including loss of dentinal tubules and enamel prisms, as well as unexpected ectopic ossification within the pulp root canal. TUNEL assay showed a sharp increase in apoptotic cells in ameloblasts and odontoblasts. Based on the above findings, we conclude that DMP1 has a protective role for odontoblasts and ameloblasts in a pro-apoptotic environment （a high Pi level）.

Aberrant DNA methylation profile in cholangiocarcinoma

Cholangiocarcinoma(CCA)is a notoriously lethal epith-elial cancer originating from the biliary system.As radical resection offers a poor success rate and limited effective adjuvant modalities exist in its advanced stage,the disease leads to a fairly poor prognosis.As the incidence of CCA is increasing,although the mortality rate remains stable,and few other definite etiologies have yet to be established,renewing our knowledge of its fundamental carcinogenesis is advisable.The latest advances in molecular carcinogenesis have highlighted the roles of epigenetic perturbations and cancer-related inflammation in CCA.This review focuses on the reciprocal effects between aberrant DNA methylation and inflammatory microenvironment in CCA.

Role of sex hormones in the modulation of cholangiocyte function

Over the last years,cholangiocytes,the cells that line the biliary tree,have been considered an important object of study for their biological properties which involves bile formation,proliferation,injury repair,fibrosis and angiogenesis.Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration.During these processes,biliary cells start to secrete different cytokines,growth factors,neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells.Several studies suggest that hormones,and in particular,sex hormones,play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease.Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases.The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology.

Effect of cytokeratin 17 on retinal pigment epithelium degeneration and choroidal neovascularization

AIM： To study the effects of cytokeratin 17 （CK17） on sodium iodate （NalOs） induced rat retinal pigment epithelium （RPE） degeneration, laser induced rat choroidal neovascularization （CNV）, and oxidative stress of human retinal pigment epithelium cells （ARPE-19） and human umbilical vein endothelial cell （HUVEC）. METHODS： Thirty 8-week-old male Brown Norway rats were randomly divided into 3 groups, 10 rats in control group treated with solvent alone; 10 rats in NalOs group treated with solvent and 35 mg/kg NalO3 injection through hypoglossal vein and 10 rats in CK17 ＋NaIOs group treated with 1% CK17 eye drop 3 times a day for lwk before and 4wk after NalOs injection. RPE function was measured with c-wave of electroretinogram （ERG）. Another 20 rats were randomly divided into 2 groups. Of them 10 rats in CK17 group were anesthetized to receive Nd：YAG laser and given 1% CK17 eye drop before same as above; 10 rats in control were received Nd：YAG and treated with solvent. The development of choroidal neovascularization （CNV） was determined by fundus fluorescein angiography （FFA） performed on 4wk after laser. Methylthiazoly tetrazolium （MTT） assay was used to study effect of CK17 on various oxidants induced injury in ARPE-19 and HUVEC /n vitro RESULTS： Four weeks after NalOs injection, the c- wave amplitude of ERG was 0.393±0.02 V in the control group, 0.184±0.018 V in NalOs group and 0.3±0.01 V in CK17＋NalOs group. There was a significant reversal of the c-wave by CK17 as compared to NalOs group （P〈0.01）. Four weeks after laser, the size of the CNV lesion was 2.57±0.27 mm2 in control group and 1.64 ±0.08 mm2 in CK17 group. The lesion size significantly diminished in CK17 group （P〈0.01）. The inn vitro results showed CK17 also reversed the various oxidants induced injuries in ARPE-19 at the dose of 100 μg/mL and enhanced the injury in HUVECs at different concentrations. CONCLUSION： CK17 can significantly protect RPE from NalOs induced degeneration in vivo and /n vito and also could reverse the various oxidants induced injuries in vitro. It inhibits the development of CNV in rat model, interfered with vascular endothelial cell proliferation in ivtro.

Effect of flavone on the ocular blood flow and formation of choroidal neovascularization

AIMTo investigate the effect of flavone on ocular blood flow in rabbit eyes and the formation of choroidal neovascularization (CNV) in rat model of age-related macular degeneration (AMD).

Acute effects of human protein S administration after traumatic brain injury in mice

Despite years of effort,no effective acute phase treatment has been discovered for traumatic brain injury.One impediment to successful drug development is entangled secondary injury pathways.Here we show that protein S,a natural multifunctional protein that regulates coagulation,inflammation,and apoptosis,is able to reduce the extent of multiple secondary injuries in traumatic brain injury,and therefore improve prognosis.Mice subjected to controlled cortical impact were treated acutely(10–15 minutes post-injury)with a single dose of either protein S(1 mg/kg)or vehicle phosphate buffered saline via intravenous injection.At 24 hours post-injury,compared to the non-treated group,the protein S treated group showed substantial improvement of edema and fine motor coordination,as well as mitigation of progressive tissue loss.Immunohistochemistry and western blot targeting caspase-3,B-cell lymphoma 2(Bcl-2)along with terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assay revealed that apoptosis was suppressed in treated animals.Immunohistochemistry targeting CD11 b showed limited leukocyte infiltration in the protein S-treated group.Moreover,protein S treatment increased the ipsilesional expression of aquaporin-4,which may be the underlying mechanism of its function in reducing edema.These results indicate that immediate intravenous protein S treatment after controlled cortical impact is beneficial to traumatic brain injury prognosis.Animal Use Protocols(AUPs)were approved by the University Committee on Animal Resources(UCAR)of University of Rochester Medical Center(approval No.UCAR-2008-102 R)on November 12,2013.

Predictors of thirty-day readmission in nonagenarians presenting with acute heart failure with preserved ejection fraction: a nationwide analysis

BACKGROUD Acute heart failure with preserved ejection fraction(HFpEF)is a common but poorly studied cause of hospital admissions among nonagenarians.This study aimed to evaluate predictors of thirty-day readmission,in-hospital mortality,length of stay,and hospital charges in nonagenarians hospitalized with acute HFpEF.METHODS Patients hospitalized between January 2016 and December 2018 with a primary diagnosis of diastolic heart failure were identified using ICD-10 within the Nationwide Readmission Database.We excluded patients who died in index admission,and discharged in December each year to allow thirty-day follow-up.Univariate regression was performed on each variable.Vari-ables with P-value<0.2 were included in the multivariate regression model.RESULTS From a total of 45,393 index admissions,43,646 patients(96.2%)survived to discharge.A total of 7,437 patients(15.6%)had a thirty-day readmission.Mean cost of readmission was 43,265 United States dollars(USD)per patient.Significant predictors of thirty-day readmission were chronic kidney disease stage III or higher[adjusted odds ratio(aOR)=1.20,95%CI:1.07−1.34,P=0.002]and diabetes mellitus(aOR=1.18,95%CI:1.07−1.29,P=0.001).Meanwhile,female(aOR=0.90,95%CI:0.82−0.99,P=0.028)and palliative care encounter(aOR=0.27,95%CI:0.21−0.34,P<0.001)were associated with lower odds of readmission.Cardiac arrhythmia(aOR=1.46,95%CI:1.11−1.93,P=0.007)and aortic stenosis(aOR=1.36,95%CI:1.05−1.76,P=0.020)were amongst predictors of in-hospital mortality.CONCLUSIONS In nonagenarians hospitalized with acute HFpEF,thirty-day readmission is common and costly.Chronic co-morbidities predict poor outcomes.Further strategies need to be developed to improve the quality of care and prevent the poor outcome in nonagenarians.

ULTRASHORT PULSE MULTISPECTRAL NON-LINEAR OPTICAL MICROSCOPY

Ultrashort pulse,multispectral non-linear optical microscopy(NLOM)is developed and used to image,simultaneously,a mixed population of cells expressing different fluorescent protein mutants in a 3D tissue model of angiogenesis.Broadband,sub-10-fs pulses are used to excite multiple fluorescent proteins and generate second harmonic in collagen.A 16-channel multispectral detector is used to delineate the multiple non-linear optical signals,pixel by pixel,in NLOM.The ability to image multiple fluorescent protein mutants and collagen,enables serial measurements of cell-cell and cell-matrix interactions in our 3D tissue model and characterization of fundamental processes in angiogenic morphogenesis.

A combination therapy for KRAS-mutant lung cancer by targeting synthetic lethal partners of mutant KRAS

The KRAS gene is frequently mutated in multiple cancer types,but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological properties.As reported in the paper entitled "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK" in Nature Communications,we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs;we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase markedly suppressed tumor growth in mice.An increase in the expression of the tumor suppressor P21^(WAF1/CIP1) contributed to the synergistic mechanism of the combination therapy.These findings open a novel avenue for the treatment of KRAS-mutant lung cancer.

Characterization of Fam20C expression in odontogenesis and osteogenesis using transgenic mice

Our previous studies have demonstrated that Fam20 C promotes differentiation and mineralization of odontoblasts,ameloblasts,osteoblasts and osteocytes during tooth and bone development.Ablation of the Fam20 C gene inhibits bone and tooth growth by increasing fibroblast growth factor 23 in serum and causing hypophosphatemia in conditional knockout mice.However,control and regulation of the expression of Fam20 C are still unknown.In this study,we generated a transgenic reporter model which expresses green fluorescence protein（GFP） driven by the Fam20 C promoter.Recombineering was used to insert a 16 kb fragment of the mouse Fam20 C gene（containing the 15 kb promoter and 1.1 kb of exon 1） intoa pBluescript SK vector with the topaz variant of GFP and a bovine growth hormone polyadenylation sequence.GFP expression was subsequently evaluated by histomorphometry on cryosections from E14 to adult mice.Fluorescence was evident in the bone and teeth as early as E17.5.The GFP signal was maintained stably in odontoblasts and osteoblasts until 4 weeks after birth.The expression of GFP was significantly reduced in teeth,alveolar bone and muscle by 8 weeks of age.We also observed colocalization of the GFP signal with the Fam20 C antibody in postnatal 1- and 7-day-old animals.Successful generation of Fam20C-GFP transgenic mice will provide a unique model for studying Fam20 C gene expression and the biological function of this gene during odontogenesis and osteogenesis.

Cesarean Section Incision Complications and Associated Risk Factors: A Quality Assurance Project

Background: Today in the United States, approximately 30% of deliveries are performed by cesarean section. Wound infections and other post-operative complications represent a frequent morbidity which may be improved with an understanding of local risk factors. Objective: This project used a retrospective analysis of cesarean section incision complications and infection events along with patient chart information to identify potential risk factors associated with incisional wound complications at our institution. Methods: ICD9 codes identified 618 cesarean sections from July 2012 through June 2013. Of these, 59 were excluded. Twelve different data elements were examined and complications were divided into two categories: presence of infection and presence of seroma/hematoma. Statistics included univariate analysis and multiple logistic regressions to identify an odds ratio for associations using P < 0.05 as significant. Results: 73 (13.1%) of 559 patients developed a post-partum incision complication. Five logistic variables were included in amultiple logistic regression model for all incision complications. Three of the five variables had a significant odds ratio: emergent cesarean section, stapled skin closure, and preeclampsia. Five logistic variables were included in another multiple logistic regression model for all wound infections. Two of the five variables had a significant odds ratio: BMI > 33.4 and preeclampsia. Conclusions: Cesarean section rates account for approximately 30% of deliveries, with significant maternal morbidity associated with incisional wound complications. This study found multiple significant risk factors for both wound complications and infections. Preeclampsia was an independent risk factor for both wound complications and infections.

Chemotherapy rechallenge in metastatic colon cancer:A case report and literature review

BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50%-60%will develop metastasis over the course of their disease.Despite advances in systemic therapies,there remains a paucity of effective third-and later-line therapies for patients with ongoing disease progression.However,rechallenging chemoresistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer(mCRC).CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness.Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease.He underwent a colectomy with anastomosis.Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma(T4bN1bM1a).He received adjuvant 5-fluorouracil,leucovorin,and oxaliplatin(FOLFOX),but therapy was discontinued due to the development of atrial fibrillation.Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL,and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type.He was started on irinotecan with oxaliplatin(IROX),and bevacizumab(14 cycles),developed disease progression,was transitioned to FOLFOX and cetuximab,and then eventually three cycles of pembrolizumab.Following disease progression,he was rechallenged with IROX therapy,as he previously responded well to oxaliplatin-based therapy.The IROX rechallenge provided this patient with a ten-month survival benefit,decreased metastatic burden,and marked improvement in his clinical condition.CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.

Overlap of diabetic ketoacidosis and hyperosmolar hyperglycemic state

Diabetic ketoacidosis(DKA)and hyperosmolar hyperglycemia state(HHS)are two life-threatening metabolic complications of diabetes that significantly increase mortality and morbidity.Despite major advances,reaching a uniform consensus regarding the diagnostic criteria and treatment of both conditions has been challenging.A significant overlap between these two extremes of the hyperglycemic crisis spectrum poses an additional hurdle.It has well been noted that a complete biochemical and clinical patient evaluation with timely diagnosis and treatment is vital for symptom resolution.Worldwide,there is a lack of large-scale studies that help define how hyperglycemic crises should be managed.This article will provide a comprehensive review of the pathophysiology,diagnosis,and management of DKA-HHS overlap.

Role of octreotide in small bowel bleeding

Gastrointestinal bleeding accounts for a drastic negative impact on the quality of the patients’lives as it requires multiple diagnostic and therapeutic interventions to identify the source of the bleeding.Small bowel bleeding is the least common cause of gastrointestinal bleeding.However,it is responsible for the majority of complaints from patients with persisting or recurring bleeding where the primary source of bleeding cannot be identified despite investigation.A somatostatin analog known as octreotide is among the medical treatment modalities currently used to manage small bowel bleeding.This medication helps control symptoms of gastrointestinal bleeding by augmenting platelet aggregation,decreasing splanchnic blood flow,and antagonizing angiogenesis.In this review article,we will highlight the clinical efficacy of octreotide in small bowel bleeding and its subsequent effect on morbidity and mortality.