Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128

Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.

Lean body mass index is a marker of advanced tumor features in patients with hepatocellular carcinoma

BACKGROUND Obesity is an independent risk factor for the development of hepatocellular carcinoma(HCC)and may influence its outcomes.However,after diagnosis of HCC,like other malignancies,the obesity paradox may exist where higher body mass index(BMI)may in fact confer a survival benefit.This is frequently observed in patients with advanced HCC and cirrhosis,who often present late with advanced tumor features and cancer related weight loss.AIM To explore the relationship between BMI and survival in patients with cirrhosis and HCC.METHODS This is a retrospective cohort study of over 2500 patients diagnosed with HCC between 2009-2019 at two United States academic medical centers.Patient and tumor characteristics were extracted manually from medical records of each institutions'cancer registries.Patients were stratified according to BMI classes:<25 kg/m^(2)(lean),25-29.9 kg/m^(2)(overweight),and>30 kg/m^(2)(obese).Patient and tumor characteristics were compared according to BMI classification.We performed an overall survival analysis using Kaplan Meier by the three BMI classes and after adjusting for Milan criteria.A multivariable Cox regression model was then used to assess known risk factors for survival in patients with cirrhosis and HCC.RESULTS A total of 2548 patients with HCC were included in the analysis of which 11.2%(n=286)were classified as noncirrhotic.The three main BMI categories:Lean(n=754),overweight(n=861),and obese(n=933)represented 29.6%,33.8%,and 36.6%of the total population overall.Within each BMI class,the non-cirrhotic patients accounted for 15%(n=100),12%(n=94),and 11%(n=92),respectively.Underweight patients with a BMI<18.5 kg/m^(2)(n=52)were included in the lean cohort.Of the obese cohort,42%(n=396)had a BMI≥35 kg/m^(2).Out of 2262 patients with cirrhosis and HCC,654(29%)were lean,767(34%)were overweight,and 841(37%)were obese.The three BMI classes did not differ by age,MELD,or Child-Pugh class.Chronic hepatitis C was the dominant etiology in lean compared to the overweight and obese patients(71%,62%,49%,P<0.001).Lean patients had significantly larger tumors compared to the other two BMI classes(5.1 vs 4.2 vs 4.2 cm,P<0.001),were more likely outside Milan(56%vs 48%vs 47%,P<0.001),and less likely to undergo transplantation(9%vs 18%vs 18%,P<0.001).While both tumor size(P<0.0001)and elevated alpha fetoprotein(P<0.0001)were associated with worse survival by regression analysis,lean BMI was not(P=0.36).CONCLUSION Lean patients with cirrhosis and HCC present with larger tumors and are more often outside Milan criteria,reflecting cancer related cachexia from delayed diagnosis.Access to care for hepatitis C virus therapy and liver transplantation confer a survival benefit,but not overweight or obese BMI classifications.

Genomics in personalized cancer medicine and its impact on earlydrug development in China: report from the 6th Annual Meeting of the US Chinese Anti-Cancer Association(USCACA) at the 50th ASCOAnnual Meeting

The 6th Annual Meeting of the United States Chinese Anti-Cancer Association(USCACA) was held in conjunction with the 50 th Annual Meeting of American Society of Clinical Oncology(ASCO) on May 30, 2014 in Chicago, Illinois, the United States of America. With a focus on personalized medicine, the conference featured novel approaches to investigate genomic aberrations in cancer cells and innovative clinical trial designs to expedite cancer drug development in biomarker-defined patient populations. A panel discussion further provided in-depth advice on advancing development of personalized cancer medicines in China. The conference also summarized USCACA key initiatives and accomplishments, including two awards designated to recognize young investigators from China for their achievements and to support their training in the United States. As an effort to promote international collaboration, USCACA will team up with Chinese Society of Clinical Oncology(CSCO) to host a joint session on "Breakthrough Cancer Medicines" at the upcoming CSCO Annual Meeting on September 20 th, 2014 in Xiamen, China.

Gender differences of lower urinary tract symptoms in older Chinese Americans

Objective To describe whether or not there are gender differences in lower urinary tract symptoms(LUTS)prevalence and risk factors in community-dwelling older Chinese Americans.Methods We performed a secondary analysis of a prospective cross-sectional population-based survey of Chinese Americans aged 60 years and older between January 2011 and December 2013 in English,Mandarin,Cantonese,Taishanese,or Teochew.A clinical review of systems was used to assess LUTS,which included urinary frequency,urgency,burning and/or pain,blood in urine,and urinary incontinence.Results Of the total 3157 people queried,42%were men and 58%were women.More men reported LUTS compared to women(32.9%vs.28.6%,p=0.01).In a multivariable analysis,female gender(adjusted odds ratio[aOR]0.60,95%confidence interval[CI]0.49-0.73),being married(aOR 0.79,95%CI 0.65-0.97),and smoking(aOR 0.66,95%CI 0.49-0.88)were found to be protective,while traditional Chinese medicine use(aOR 1.51,95%CI 1.28-1.78),heart disease(aOR 1.54,95%CI 1.24-1.91),and anxiety(aOR 1.69,95%CI 1.25-2.28)were most strongly associated with increased odds of LUTS.When examining genders separately,being married was found to be protective only in women.Meanwhile,unique factors found in men were hypertension,heart disease,and practice of Tai Chi.Conclusion In this large population-based study,LUTS were more prevalent in older Chinese American men than women.We also found gender-specific factors that influenced the odds of reporting LUTS;however,traditional Chinese medicine use was the only factor that was shared by both genders.Future longitudinal investigations are needed to elucidate these underlying mechanisms to provide evidence-based and culture-specific guidelines for this rapidly growing population.

Comments by opponents on the British Medical Association’s guidance on non-therapeutic male circumcision of children seem one-sided and may undermine public health

The British Medical Association(BMA)guidance on non-therapeutic circumcision(NTMC)of male children is limited to ethical,legal and religious issues.Here we evaluate criticisms of the BMA’s guidance by Lempert et al.While their arguments promoting autonomy and consent might be superficially appealing,their claim of high procedural risks and negligible benefits seem one-sided and contrast with high quality evidence of low risk and lifelong benefits.Extensive literature reviews by the American Academy of Pediatrics and the United States Centers for Disease Control and Prevention in developing evidence-based policies,as well as risk-benefit analyses,have found that the medical benefits of infant NTMC greatly exceed the risks,and there is no reduction in sexual function and pleasure.The BMA’s failure to consider the medical benefits of early childhood NTMC may partly explain why this prophylactic intervention is discouraged in the United Kingdom.The consequence is higher prevalence of preventable infections,adverse medical conditions,suffering and net costs to the UK’s National Health Service for treatment of these.Many of the issues and contradictions in the BMA guidance identified by Lempert et al stem from the BMA’s guidance not being sufficiently evidence-based.Indeed,that document called for a review by others of the medical issues surrounding NTMC.While societal factors apply,ultimately,NTMC can only be justified rationally on scientific,evidence-based grounds.Parents are entitled to an accurate presentation of the medical evidence so that they can make an informed decision.Their decision either for or against NTMC should then be respected.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Extracellular vesicles and angiotensin-converting enzyme 2 in COVID-19 disease

Extracellular vesicles(EVs)are membranous vesicular structures released from almost all eukaryotic cell types under different physiological or pathological conditions.Growing evidence demonstrates that EVs can serve as mediators of intercellular communication between donor and recipient cells or microorganism-infected and noninfected cells.Coronavirus disease 2019(COVID-19)disease is caused by infection of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)of host cells in the respiratory system and various extra-pulmonary tissue/organs,resulting in complications of multiple organ systems.As the cell surface receptor,angiotensin-converting enzyme 2(ACE2)mediates cellular entry of SARS-CoV-2 into the host cells in patients with COVID-19.Recent studies have found that ACE2 can be released with EVs,which have been shown to interfere with the entry of the virus into host cells and thus may be involved in COVID-19 pathophysiology.In addition,ACE2,neprilysin(NEP),and thimet oligopeptidase(TOP)are the key enzymes that regulate angiotensin metabolism by converting angiotensin II or angiotensin I to angiotensin 1-7,the latter of which has protective effects in counterbalancing the harmful effects of angiotensin II in COVID-19 disease.This review summarizes the recent research progress regarding EV-associated ACE2,NEP,and TOP and the perspectives of their potential involvement in the pathophysiology of COVID-19 disease.

Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases in children and adolescents.NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis(NASH),wherein hepatocellular inflammation and/or fibrosis coexist with steatosis.Circulating microRNA(miRNA)levels have been suggested to be altered in NAFLD,but the extent to which miRNA are related to NAFLD features remains unknown.This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents.AIM To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD.METHODS This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study.Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD.Plasma samples were collected during surgery for miRNA profiling.A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform.We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age,sex,race,and other key covariates.Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD.RESULTS We identified 16 upregulated plasma miRNAs,including miR-193a-5p and miR-193b-5p,and 22 downregulated plasma miRNAs,including miR-1282 and miR-6734-5p,in adolescents with NAFLD.Moreover,52,16,15,and 9 plasma miRNAs were associated with NASH,fibrosis,ballooning degeneration,and lobular inflammation,respectively.Collectively,16 miRNAs were associated with two or more histological features of NAFLD.Among those miRNAs,miR-411-5p was downregulated in NASH,ballooning,and fibrosis,while miR-122-5p,miR-1343-5p,miR-193a-5p,miR-193b-5p,and miR-7845-5p were consistently and positively associated with all histological features of NAFLD.Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression,while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B.CONCLUSION Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity.Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.

Physical activity as a treatment of non-alcoholic fatty liver disease:A systematic review

AIM: To review the effectiveness of exercise as a therapy for nonalcoholic fatty liver disease(NAFLD) and potential benefits in treating insulin resistance and atherosclerosis.METHODS: Medline(EBSCOhost) and Pub Med were searched for English-language randomized controlled trials and prospective cohort studies in human adults aged ≥ 18 which investigated the various effects of exercise alone, a combination of exercise and diet, or exercise and diet coupled with behavioral modification on NAFLD from 2010 to Feburary 2015.RESULTS: Eighteen of 2298 available studies were chosen for critical review, which included 6925 patients. Nine(50%) studies were randomized controlled trials. Five(27.8%) studies utilized biopsy to examine the effects of physical activity on hepatic histology. The most commonly employed imaging modality to determine change in hepatic steatosis was hydrogen-magnetic resonance spectroscopy. Only two studies examined the effects of low impact physical activity for patients with significant mobility limitations and one compared the efficacy of aerobic and resistance exercise. No studies examined the exact duration of exercise required for hepatic and metabolic improvement in NAFLD.CONCLUSION: While exercise improved hepatic steatosis and underlying metabolic abnormalities in NAFLD, more studies are needed to define the most beneficial form and duration of exercise treatment.

Epidemiological transition of colorectal cancer in developing countries: Environmental factors, molecular pathways, and opportunities for prevention

Colorectal cancer(CRC)is one of the leading causes of cancer and cancer-related mortality worldwide.The disease has been traditionally a major health problem in industrial countries,however the CRC rates are increasing in the developing countries that are undergoing economic growth.Several environmental risk factors,mainly changes in diet and life style,have been suggested to underlie the rise of CRC in these populations.Diet and lifestyle impinge on nuclear receptors,on the intestinal microbiota and on crucial molecular pathways that are implicated in intestinal carcinogenesis.In this respect,the epidemiological transition in several regions of the world offers a unique opportunity to better understand CRC carcinogenesis by studying the disease phenotypes and their environmental and molecular associations in different populations.The data from these studies may have important implications for the global prevention and treatment of CRC.

Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase

The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2(COX-2) and 5-lipoxygenase(5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo.The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

The role of the androgen receptor in prostate development and benign prostatic hyperplasia:A review

Benign prostatic hyperplasia(BPH)is a benign enlargement of the prostate in which incidence increases linearly with age,beginning at about 50 years old.BPH is a significant source of morbidity in aging men by causing lower urinary tract symptoms and acute urinary retention.Unfortunately,the etiology of BPH incidence and progression is not clear.This review highlights the role of the androgen receptor(AR)in prostate development and the evidence for its involvement in BPH.The AR is essential for normal prostate development,and individuals with defective AR signaling,such as after castration,do not experience prostate enlargement with age.Furthermore,decreasing dihydrotestosterone availability through therapeutic targeting with 5a-reductase inhibitors diminishes AR activity and results in reduced prostate size and symptoms in some BPH patients.While there is some evidence that AR expression is elevated in certain cellular compartments,how exactly AR is involved in BPH progression has yet to be elucidated.It is possible that AR signaling within stromal cells alters intercellular signaling and a“reawakening”of the embryonic mesenchyme,loss of epithelial AR leads to changes in paracrine signaling interactions,and/or chronic inflammation aids in stromal or epithelial proliferation evident in BPH.Unfortunately,a subset of patients fails to respond to current medical approaches,forcing surgical treatment even though age or associated co-morbidities make surgery less attractive.Fundamentally,new therapeutic approaches to treat BPH are not currently forthcoming,so a more complete molecular understanding of BPH etiology is necessary to identify new treatment options.

Proliferation and phenotypic changes of stromal cells in response to varying estrogen/androgen levels in castrated rats

It is known that human benign prostatic hyperplasia might arise from an estrogen/androgen （E/T） imbalance. We studied the response of castrated rat prostate to different ratios of circulating E/T. The castrated male Wistar rats were randomly injected with E/T at different ratios for 4 weeks. The prostates of E/T （1：100） group showed a distinct prostatic hyperplasia response by prostatic index, hematoxylin and eosin staining, and quantitative immunohistochemical analysis of a-smooth muscle actin （SMA）. In this group, cells positive for Vimentin, non-muscle myosin heavy chain （NMMHC） and proliferating cell nuclear antigen （PCNA） increased in the stroma and epithelium. Furthermore, the mRNA levels of smooth muscle myosin heavy chain （SMMHC） and NMMHC increased. So E/T at a ratio of 1：100 can induce a stromal hyperplastic response in the prostate of castrated rats. The main change observed was an increase of smooth muscle cells, whereas some epithelial changes were also seen in the rat prostates.

Chemotherapy response evaluation in a mouse model of gastric cancer using intravoxel incoherent motion diffusionweighted MRI and histopathology

AIM To determine the role of intravoxel incoherent motion(IVIM) diffusion-weighted(DW) magnetic resonance imaging(MRI) using a bi-exponential model in chemotherapy response evaluation in a gastric cancer mouse model.METHODS Mice bearing MKN-45 human gastric adenocarcinoma xenografts were divided into four treated groups(TG1, 2, 3 and 4, n = 5 in each group) which received Fluorouracil and Calcium Folinate and a control group(CG, n = 7). DW-MRI scans with 14 b-values(0-1500 s/mm2) were performed before and after treatment on days 3, 7, 14 and 21. Fast diffusion component(presumably pseudo-perfusion) parameters including the fast diffusion coefficient(D*) and fraction volume(f p), slow diffusion coefficient(D) and the conventional apparent diffusion coefficients(ADC) were calculated by fitting the IVIM model to the measured DW signals. The median changes from the baseline to each posttreatment time point for each measurement(ΔADC, ΔD* and Δf p) were calculated. The differences in the median changes between the two groups were compared using the mixed linear regression model by the restricted maximum likelihood method shown as z values. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. The median percentage changes were compared with the histopathological analyses between the pre-and post-treatment for each measurement.RESULTS Compared with the control group, D* in the treated group decreased significantly(ΔD*treated% =-30%,-34% and-20%, with z =-5.40,-4.18 and-1.95. P = 0.0001, 0.0001 and 0.0244) and f p increased significantly(Δfptreated% = 93%, 113% and 181%, with z = 4.63, 5.52, and 2.12, P = 0.001, 0.0001 and 0.0336) on day 3, 7 and 14, respectively. Increases in ADC in the treated group were higher than those in the control group on days 3 and 14(z = 2.44 and 2.40, P = 0.0147 and P = 0.0164). CONCLUSION Fast diffusion measurements derived from the biexponential IVIM model may be more sensitive imaging biomarkers than ADC to assess chemotherapy response in gastric adenocarcinoma.

psychosocial impact of irritable bowel syndrome: A brief review

Irritable bowel syndrome(IBS) is a common disorder of the gastrointestinal tract with unclear etiology and no reliable biomarker. Like other chronic and functional disorders, medical treatments for IBS are suboptimal and the overall illness burden is high. Patients with IBS report high rates of psychopathology, low quality of life, and increased suicidal ideation. These patients also miss more days of work, are less productive at work, and use many healthcare resources. However, little is known about the burden of IBS on daily functioning. The primary aim of this paper is to review the current literature on the burden of IBS and to highlight the need for further research to evaluate the impact of IBS on daily activities. This research would contribute to our existing understanding of the impact of IBS on overall quality of life and well-being.

Risk of colon cancer in hereditary non-polyposis colorectal cancer patients as predicted by fuzzy modeling:Influence of smoking

瞄准：为了调查一个模糊逻辑模型是否能预言肤色，表面的癌症(CRC ) 风险由在世袭 non-polyposis 肤色吸表面的癌症(HNPCC ) 病人产生了。方法：从 Creighton 大学世袭癌症研究所登记的 340 个 HNPCC 失配修理(MMR ) 变化搬运人为当模特儿被选择。年龄依赖者曲线被产生阐明开发 CRC 的概率上的在基因变化(hMLH1 或 hMSH2 ) 之间的联合效果，性，和吸烟地位。结果：在男 hMSH2 变化搬运人的吸烟显著地增加的 CRC 风险(P 【 0.05 ) 。hMLH1 变化为男性相对 hMSH2 变化搬运人扩充了 CRC 风险(P 【 0.05 ) 。男性们非为 hMLH1 比女性有 CRC 的显著地更高的风险吸烟者(P 【 0.05 ) ， hMLH1 吸烟者(P 【 0.1 ) 并且 hMSH2 吸烟者(P 【 0.1 ) 。以在在男性的 hMSH2 的一种剂量依赖者方式的吸烟支持的 CRC (P 【 0.05 ) 。有 hMSH2 变化的女性和与 hMLH1 组一起的两性仅仅在广泛的吸烟历史以后表明了吸烟效果(P 【 0.05 ) 。结论：由在 HNPCC 病人吸烟的 CRC 提升依赖于基因变化，性和年龄。这些数据证明模糊建模可以启用临床的风险分数的明确的表达，从而允许 CRC 预防策略的 individualization。

Regenerative medicine based applications to combat stress urinary incontinence

Stress urinary incontinence(SUI), as an isolated symptom, is not a life threatening condition. However, the fear of unexpected urine leakage contributes to a significant decline in quality of life parameters for afflicted patients. Compared to other forms of incontinence, SUI cannot be easily treated with pharmacotherapy since it is inherently an anatomic problem. Treatment options include the use of bio-injectable materials to enhance closing pressures, and the placement of slings to bolster fascial support to the urethra. However, histologic findings of degeneration in the incontinent urethral sphincter invite the use of tissues engineering strategies to regenerate structures that aid in promoting continence. In this review, we will assess the role of stem cells in restoring multiple anatomic and physiological aspects of the sphincter. In particular, mesenchymal stem cells and CD34+cells have shown great promise to differentiate into muscular and vascular components,respectively. Evidence supporting the use of cytokines and growth factors such as hypoxia-inducible factor1-alpha, vascular endothelial growth factor, basic fi-broblast growth factor, hepatocyte growth factor and insulin-like growth factor further enhance the viability and direction of differentiation. Bridging the benefits of stem cells and growth factors involves the use of synthetic scaffolds like poly(1,8-octanediol-co-citrate)(POC) thin films. POC scaffolds are synthetic, elastomeric polymers that serve as substrates for cell growth,and upon degradation, release growth factors to the microenvironment in a controlled, predictable fashion.The combination of cellular, cytokine and scaffold elements aims to address the pathologic deficits to urinary incontinence, with a goal to improve patient symptoms and overall quality of life.

Dyslipidemia management in primary prevention of cardiovascular disease:Current guidelines and strategies

Cardiovascular disease is the leading cause of death in the United States. In 2010, the Centers for Disease Control and Prevention estimated that $444 billion was spent on cardiovascular diseases alone, about $1 of every $6 spent on health care. As life expectancy continues to increase, this annual cost will also increase, making costeffective primary prevention of cardiovascular disease highly desirable. Because of its role in development of atherosclerosis and clinical events, dyslipidemia management is a high priority in cardiovascular prevention. Multiple major dyslipidemia guidelines have been published around the world recently, four of them by independent organizations in the United States alone. They share the goal of providing clinical guidance on optimal dyslipidemia management, but guidelines differ in their emphasis on pharmacotherapy, stratification of groups, emphasis on lifestyle modification, and use of a fixed target or percentage reduction in low density lipoprotein cholesterol. This review summarizes eight major guidelines for dyslipidemia management and considers the basis for their recommendations. Our primary aim is to enhance understanding of dyslipidemia management guidelines in patient care for primary prevention of future cardiovascular risk.

Induction of therapeutic hypothermia via the esophagus:a proof of concept study

BACKGROUND:Induction of hypothermia(a 4℃decrease from baseline)improves outcomes in adult cardiac arrest and neonatal hypoxic ischemic encephalopathy,and may benefit other conditions as well.Methods used to implement or prevent hypothermia typically require skin contact with blankets or pads or intravascular access with catheter devices.The study was to evaluate the potential to induce mild therapeutic hypothermia via an esophageal route in a porcine model.METHODS:Single-animal proof-of-concept study of a prototype esophageal device in a 70 kg Yorkshire swine.We measured the rate of temperature change after placement of a prototype device to induce hypothermia via the esophagus,and compared this rate to known temperature changes that occur under similar laboratory conditions without a hypothermic device.RESULTS:Swine temperature decreased from a starting temperature of 37.8℃to 33.8℃(achieving the goal of a 4℃decrease)in 175 minutes,resulting in a cooling rate of 1.37℃/h.Histopathology of the esophagus showed normal tissue without evidence of injury.CONCLUSION:A prototype of an esophageal cooling device induced hypothermia effectively in a large single-swine model.

Highlights of the physical examination in heart failure

Because decompensated heart failure (HF) patients present primarily with symptoms of congestion, the assessment of volume status is of paramount importance. Despite the addition of new technologies that can predict intracardiac filling pressures, the physical exam (PE) remains the most accessible and cost-effective tool available to clinicians. An elevated jugular venous pressure (JVP)useful cutoff is that if the JVP is greater than 3 cm in vertical distance above the sternal angle, the central venous pressure is elevated. In addition to assessment of volume status, the PE in HF can reveal adverse prognostic signs, namely: elevated JVP, presence of third heart sound, elevated heart rate, low systolic BP, and low proportional pulse pressure (＜ 25%). This article will review the evidence for the diagnostic and prognostic utility of common PE findings in HF.