Management of cerebral amyloid angiopathy and atrial fibrillation:We are still far from precision medicine

The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy(CAA)and atrial fibrillation(AF).In fact,CAA is an age-related cerebral vasculopathy that predisposes patients to intracerebral hemorrhage.Nevertheless,many AF patients require oral systemic dose-adjusted warfarin,direct oral anticoagulants(such as factor Xa inhibitors)or direct thrombin inhibitors to control often associated with cardioembolic stroke risk.The prevalence of both CAA and AF is expected to rise,due to the aging of the population.This clinical dilemma is becoming increasingly common.In patients with coexisting AF and CAA,the risks/benefits profile of anticoagulant therapy must be assessed for each patient individually due to the lack of a clear-cut consensus with regard to its risks in scientific literature.This review aims to provide an overview of the management of patients with concomitant AF and CAA and proposes the implementation of a risk-based decision-making algorithm.

Cellular and molecular mechanisms of intestinal fibrosis

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases(IBD),including ulcerative colitis(UC) and Crohn's disease(CD),are chronic,progressive and disabling disorders.Over the last few decades,new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD.The identification of clinical,genetic and serological prognostic factors has permitted a better stratification of the disease,thus allowing the opportunity to indicate the most appropriate therapy.Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change,at least in the short term,the course of the disease by reducing,in a subset of patients with IBD,hospitalization and the need for surgery.In this review,the crucial steps in the natural history of both UC and CD will be discussed,as well as the factors that may change their clinical course.The methodological requirements for high quality studies on the course and prognosis of IBD,the true impact of environmental and dietary factors on the clinical course of IBD,the clinical,serological and genetic predictors of the IBD course(in particular,which of these are rel-evant and appropriate for use in clinical practice),the impact of the various forms of medical treatment on the IBD complication rate,the role of surgery for IBD in the biologic era,the true magnitude of risk of colorectal cancer associated with IBD,as well as the mortality rate related to IBD will be stressed;all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.

Evaluation of thermal water in patients with functional dyspepsia and irritable bowel syndrome accompanying constipation

瞄准：与机能性消化不良或伴随占优势的便秘的急躁的肠症候群(IBS ) 在病人评估水补充治疗的功效。方法：有机能性消化不良的 3872 个病人和有急躁的肠症候群的 3609 个病人的一个总数被 18 个 Italina 热中心在学习注册。病人们为 21 d 经历了热治疗的第一个周期。一年以后，病人们在一样的中心被重新估计并且收到了热治疗的另一个周期。在社会、职业的地位，家庭和病理学的病历，生活方式，临床的记录，福利的利用和健康结构和设备上收集个人数据的一张问询表在各热的治疗以后在基础时间和一年予每个病人被以。有机能性消化不良的六十个病人并且 20 由呼吸测试分析与 IBS 和 80 健康控制收到了胃的输出和 oro 盲肠的运输时间的评估。呼吸测试在基础时间并且在水补充治疗以后被执行。胃肠的症状同时被评估点。呼吸样品与集体 spectometer 和 gascromatograph 被分析。结果为呼吸测试的 octanoic 和 lactulose 呼吸测试的同样 oro 盲肠的运输时间被表示为 T (1/2 ) 和 T 落后。结果：症状的流行的重要减小在热治疗的第一和第二个周期的结束被观察在消化不良并且 IBS 病人。变化的分析出现了一真实并且在所有病人坚持症状的蚂蚁改进。在为 3 wk 的水补充以后，胃的输出的减小在 49 被观察(87.5%) 56 个消化不良的病人。T (1/2 ) 和 T 落后显著地与基础价值相比在治疗以后被减少[91 +/- 12 T (1/2 ) 和 53 +/- 11 (T 落后) ，搁置 1 和 2 ] 与类似于健康题目的 octanoic 呼吸测试的结果。在为 3 wk 的水补充以后， oro 盲肠的运输时间在学习的开始是比那短的。结论：为伴随 IBS 的机能性消化不良或便秘的矿水补充治疗能改进胃的酸输出和肠的运输时间。

Estrogens and the pathophysiology of the biliary tree

有关不同纸巾上的雌激素效果的科学框架在最后十年期间极其膨胀了，当时雌激素受体(嗯) 子类型被识别。雌激素是不仅必要的因为雌性生殖系统，而且他们也包括心血管系统，骨头，大脑和肝在另外的纸巾控制基本功能。最近，在他们调制 cholangiocytes 的增生的和分泌活动的地方，雌激素被显示了指向胆汁的树，上皮细胞衬里胆汁管。由在两雌激素受体(ER-alpha ) 并且(上扮演嗯贝它) 子类型，并且由激活 genomic 或 non-genomic 小径，雌激素在生长因素和 cytokines 的复杂的环起一个关键作用，它调制 cholangiocytes 的增生的反应损坏。明确地，雌激素激活细胞内部的发信号的串联[英皇家空军之阶级最低之兵( 1/2 )(细胞外的调整家族 ases ( 1/2 )，PI3- kinase/AKT (phosphatidylinositol-3' kinase/AKT )]典型地代表象象生长因素( IGF1 )一样的胰岛素那样的生长因素，神经生长因素( NGF )和脉管的内皮生长因素( VEGF )，因此加强他们的行动。另外，雌激素在增殖的 cholangiocytes 刺激不同生长因素的分泌物。这评论明确地处理与雌激素处于正常、病理学的条件由调制 cholangiocyte 功能的角色和机制有关的最近的进展。

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.

Mathematical model of absorption and hybrid heat pump

Recovering waste heat from industrial processes is bene ficial in order to reduce the primary energy demands and heat pumps can be used to this purpose.Absorption heat pumps are energy-saving and environment-friendly because use working fluids that do not cause ozone depletion and can reduce the global warming emissions.The hybrid heat pump processes combine the conventional vapor-compression and the absorption heat pump cycles.Studies about the simulations and modeling of hybrid heat pumps are few in literature.In this research a mathematical model for single effect absorption and hybrid heat pump is carried out with Chem Cad? 6.0.1.LiBr–H_2O is used as working fluid while electrolytic NRTL and electrolytes latent heat are used as thermodynamic model due to the better results.Binary parameters of activity coef ficients are regressed from experimental vapor pressure data while default constants are used for the solubility expressions.A design of heat pumps is developed and a new modeling of generator is analyzed.The coef ficient of performance of absorption heat pump and hybrid heat pump is equal to 0.7 and 0.83 respectively.For absorption heat pump a sensitivity analysis is carried out to evaluate the effect of temperature and pressure generator,the concentration of Li–Br solution on coef ficient of performance,cooling capacity and working fluid temperature.For hybrid heat pump,the different coef ficients of performance,the primary energy ratio,the generator heat,and the compressor power are analyzed for different values of compressor proportion.Results show that comparing the two systems the hybrid pump allows to save more primary energy,costs and carbon dioxide emissions with respect to absorption heat pump with the increasing of compressor proportion parameter.Future researches should focus on the construction of this heat pumps integrated in chemical processes as a biogas plant or trigeneration systems.

Comparison between the seismic response of 2D and 3D models of rigid blocks

A three-dimensional rigid body on the shape of a parallelepiped is modelled in order to rock on a side or a vertex of the base,in order to evaluate the seismic response of rigid blocks lying on a horizontal support.The center of mass of the body is considered as eccentric with respect to its geometric center.As seismic input,three Italian recorded accelerograms,with different spectral content,are used.The study is mainly conducted to highlight the differences between the seismic response of 2D and 3D models of rigid blocks,with the aim to understand if,in some cases,the use of the 3D model of rigid block is required to obtain safer results.In fact,the outcomes show that in some ranges of the geometrical and mechanical parameters that characterize the excitation and the body,a two-dimensional model,which is not able to consider the 3D rocking on a vertex,can provide unsafe results.In particular,it is found that the overturning process of the three-dimensional block can occur under excitations which are lower than those which overturn a corresponding two-dimensional block.

The use of choline in association with the Bangerter filters for the treatment of amblyopia

The study investigated the effects of choline combined with Bangerter filter in the treatment of amblyopia. All amblyopic subjects used a Bangerter filter on the corrective spectacle lens（1 d over the left eye, 1 d over the right eye）. Choline was then administered orally to 39 patients once daily, five days per week for the entire study period. Subjects treated with the Bangerter filter showed a mean visual acuity of 0.27 logM AR; at 12 mo of treatment, the mean visual acuity reached 0.09 log MAR. Patients treated with the Bangerter filter and citicoline showed a mean visual acuity of 0.35 log MAR; at 12 mo of treatment, the mean visual acuity reached 0.01 logMAR. No significant changes in the angle of deviation were observed in both groups. Subjects in both forms of amblyopia therapies demonstrated an increase in visual acuity. However, these effects were markedly enhanced when coupled with the administration of choline. Findings suggest that the effects are particularly relevant in the more severe amblyopic cases.

Ketoprofen,peginterferon 2a and ribavirin for genotype 1 chronic hepatitis C:A phaseⅡ study

AIM:To evaluate the safety of adding ketoprofen to pegylated-interferon(PEG-IFN)with or without ribavirin and the effect on viral kinetics,STAT1 activity and expression of 2'-5'-oligoadenylate synthetase (2'-5'OAS)in genotype 1 chronic hepatitis C in a phaseⅡstudy. METHODS:Forty-five patients were studied:fifteen were randomized to PEG-IFN plus ribavirin(PR),16 to PEGIFN plus ketoprofen and 14 to PR and ketoprofen.Themolecular study of IFN-dependent signal transduction was conducted in 9 patients from each group. RESULTS:The combination of ketoprofen and PEG- IFN with or without ribavirin was safe and well tolerated.An early activation of STAT1 was observed in ke-toprofen-treated patients,but this activation was less sustained over time.Conversely,ketoprofen plus PEG- IFN and ribavirin induced an early and sustained increase of 2'-5'OAS transcription starting 24 h after the first dose until the 36th wk.These data are consistent with the clinical results,showing a better sustained virological response and a lower relapse rate in patients receiving ketoprofen plus PEG-IFN and ribavirin. CONCLUSION:The addition of ketoprofen to the standard therapy of chronic hepatitis C should be explored in larger randomized clinical studies.

CONCENTRATION PARTITION OF PROTEIN SOLUTION IN A MICROPORE:EFFECT OF ELECTROSTATIC INTERACTION

A theory for calculating the electrostatic interaction between protein molecules and the wallof a liquid-filled micropore is established in terms of solving the Laplace and the linearPoisson-Boltzmann equations.The surface charge of protein molecules is measured by theelectrophoresis velocity,whilethe charge of the pore wall is obtained by the ionic Donnan equilibrium.The theory is then used to study the influence of solute-pore electrostatic interaction on theconcentration partition of protein solution in a micropore under different solution properties.Experi-mental verification is performed by detecting the hindered diffusion of bovine serum albumin in thetrack-etched polycarbonate membranes.A good consistence between the theoretical and experimentaldata is being achieved.

Carbon sequestration capability of Fagus sylvatica forests developing in the Majella National Park (Central Apennines,Italy)

Terrestrial ecosystems represent a major sink for atmospheric carbon(C) and temperate forests play an important role in global C cycling, contributing to lower atmospheric carbon dioxide(CO2) concentration through photosynthesis. The Intergovernmental Panel of Climate Change highlights that the forestry sector has great potential to decrease atmospheric CO2concentration compared to other sectoral mitigation activities. The aim of this study was to evaluate CO2sequestration(CO2S)capability of Fag us sylvatica(beech) growing in the Orfento Valley within Majella National Park(Abruzzo,Italy). We compared F. sylvatica areas subjected to thinning(one high-forest and one coppice) and no-management areas(two high-forests and two coppices). The results show a mean CO2S of 44.3 ± 2.6 Mg CO2ha-1a-1,corresponding to 12.1 ± 0.7 Mg C ha-1a-1the no-managed areas having a 28% higher value than the managed areas. The results highlight that thinning that allows seed regeneration can support traditional management practices such as civic use in some areas while no management should be carried out in the reserve in order to give priority to the objective of conservation and naturalistic improvement of the forest heritage.

EFFICACY AND SAFETY OF BIMATO- PROST IN PATIENTS WITH UNCON- TROLLED GLAUCOMA ON MAXIMAL TOLERABLE MEDICAL THERAPY

Purpose: to evaluate the efficacy and safety of bimatoprost as alternative to filtration surgery in patients with uncontrolled glaucoma on maximal tolerable medical therapy (MTMT). Methods: 83 consecutive patients (83 eyes), recruited from the waiting lists for glaucoma surgery of 8 ophthalmic centers. All the patients were scheduled for surgery because of inefficacy of the MTMT, and/or a progressive deterioration of the visual field. In all pa-

GLOBAL EXISTENCE OF SOLUTIONS FOR A MULTI-PHASE FLOW: A BUBBLE IN A LIQUID TUBE AND RELATED CASES

In this paper we study the problem of the global existence （in time） of weak entropic solutions to a system of three hyperbolic conservation laws, in one space dimension, for large initial data. The system models the dynamics of phase transitions in an isothermal fluid; in Lagrangian coordinates, the phase interfaces are represented as stationary contact discontinuities. We focus on the persistence of solutions consisting in three bulk phases separated by two interfaces. Under some stability conditions on the phase configuration and by a suitable front tracking algorithm we show that, if the BV-norm of the initial data is less than an explicit （large） threshold, then the Cauchy problem has global solutions.

Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes

Histamine has long been known to be involved in inflammatory events.The discovery of antihistamines dates back to the first half of the 20th century when a Swiss-Italian pharmacologist,Daniel Bovet began his work.In 1957 he was awarded a Nobel Prize for his production of antihistamines for allergy relief.Since that time,histamine has been found to play a role in other events besides allergic reaction.Possiblyun believable to Bovet and his peers,histamine has now been marked as playing a role in liver pathologies including hepatobiliary diseases.

Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer:A multicenter retrospective observational comparative study

BACKGROUND Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy(CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electrohyperthermia(mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer.AIM To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer.METHODS This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer(stage Ⅲ and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128(59%) of them were treated with CHT(no-mEHT) and 89(41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT.RESULTS Median patients’ age was 67 years(range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group(20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses(45% vs 24%, P = 0.0018) and a lower number of progressions(4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions.CONCLUSION mEHT seems safe and has beneficial effects on survival and tumor response of stage Ⅲ-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

Systemic inflammation and immune response after laparotomy vs laparoscopy in patients with acute cholecystitis, complicated by peritonitis

AIM: To evaluate acute cholecystitis, complicated by peritonitis, acute phase response and immunological status in patients treated by laparoscopic or open approach. METHODS: From January 2002 to May 2012, we conducted a prospective randomized study on 45 consecutive patients (27 women, 18 men; mean age 58 years). These subjects were taken from a total of 681 patients who were hospitalised presenting similar preoperative findings: acute upper abdominal pain with tenderness, involuntary guarding under the right hypochondrium and/or in the flank; fever higher than 38 ℃, leukocytosis greater than 10 × 10 9 /L or both, and ultrasonographic evidence of calculous cholecystitis possibly complicated by peritonitis. These patients had undergone cholecystectomy for acute calculous cholecystitis,complicated by bile peritonitis. Randomly, 23 patients were assigned to laparoscopic cholecystectomy (LC), and 22 patients to open cholecystectomy (OC). Blood samples were collected from all patients before operation and at days 1, 3 and 6 after surgery. Serum bacteraemia, endotoxaemia, white blood cells (WBCs), WBC subpopulations, human leukocyte antigen-DR (HLA-DR), neutrophil elastase, interleukin-1 (IL-1) and IL-6, and C-reactive protein (CRP) were measured at 0, 30, 60, 90, 120 and 180 min, at 4, 6, 12, 24 h, and then daily (8 A.M.) until post-operative day 6.RESULTS: The two groups were comparable in the severity of peritoneal contamination as indicated by the viable bacterial count (open group = 90% of positive cultures vs laparoscopic group = 87%) and endotoxin level (open group = 33.21 ± 6.32 pg/mL vs laparoscopic group = 35.02 ± 7.23 pg/mL). Four subjects in the OC group (18.1%) and 1 subject (4.3%) in the LC group (P < 0.05) developed intra-abdominal abscess. Severe leukocytosis (range 15.8-19.6/mL) was observed only after OC but not after LC, mostly due to an increase in neutrophils (days 1 and 3, P < 0.05). This value returned to the normal range within 3-4 d after LC and 5-7 d after OC. Other WBC types and lymphocyte subpopulations showed no significant variation. On the first day after surgery, a statistically significant difference was observed in HLA-DR expression between LC (13.0 ± 5.2) and OC (6.0 ± 4.2) (P < 0.05). A statistically significant change in plasma elastase concentration was recorded post-operatively at days 1, 3, and 6 in patients from the OC group when compared to the LC group (P < 0.05). In the OC group, the serum levels of IL-1 and IL-6 began to increase considerably from the first to the sixth hour after surgery. In the LC group, the increase of serum IL-1 and IL-6 levels was delayed and the peak values were notably lower than those in the OC group. Significant differences between the groups, for these two cytokines, were observed from the second to the twenty-fourth hour (P < 0.05) after surgery. The mean values of serum CRP in the LC group on post-operative days (1 and 3) were also lower than those in the OC group (P < 0.05). Systemic concentration of endotoxin was higher in the OC group at all intra-operative sampling times, but reached significance only when the gallbladder was removed (OC group = 36.81 ± 6.4 ρg/mLvs LC group = 16.74 ± 4.1 ρg/mL, P < 0.05). One hour after surgery, microbiological analysis of blood cultures detected 7 different bacterial species after laparotomy, and 4 species after laparoscopy (P < 0.05). CONCLUSION: OC increased the incidence of bacteraemia, endotoxaemia and systemic inflammation compared with LC and caused lower transient immunological defense, leading to enhanced sepsis in the patients examined.

Cholangiocytes and blood supply

胆汁的树的微脉管的供应，仙子胆管丛(PBP ) ，源自肝的动脉树枝和流动进肝窦状隙。PBP 的详细三维的研究被使用扫描电子执行了显微镜学脉管的腐蚀演员组(SEMvcc ) 技术。认为 PBP 在支持胆汁的上皮的能分泌、吸收性的功能起一个基本作用，他们在常态和病理的组织被探索。正常的肝证明 PBP 安排在 extra-附近 -- 并且肝内的胆汁的树。在小门道， PBP 被日益增多地继续了它显示出一个更复杂的脉管的网络的额外的肝的 PBP 的 capillaries 的单个层描绘。在普通的管结扎(BDL ) 以后，胆汁管和 PBP 增长的进步修正被观察。PBP 介绍在许多胆汁管附近安排的一个三维的网络并且作为容器的捆出现，由有典型圆网孔结构的同类的直径的 capillaries 镇静。PBP 网络从显得正常的正弦曲线网络是容易可区分的。在 BDL 期间考虑 PBP 的庞大的延期，脉管的内皮生长因素(VEGF ) 起的可能的作用被评估。VEGF -- A， VEGF-C 和他们的相关受体高度出现了在 BDL 老鼠的增殖的 cholangiocytes 积极的免疫。到象肝的动脉结扎一样的 BDL 老鼠的 anti-VEGF-A 或 anti-VEGF-C 抗体的管理导致了一个减少的胆汁管团。rVEGF 的管理 -- 到 BDL 肝的动脉的 A 绑扎老鼠阻止了 cholangiocyte 增长和 VEGF 的减少 -- 表情作为与 BDL 控制老鼠相比。这些数据处于 cholangiocyte 增长的条件建议胆汁的树的动脉的血供给的角色，例如它发生在长期的胆汁郁积期间。在另一方面， VEGF 作为在 cholangiocytes 和 PBP endothelial 之间的串音的一个工具起的作用建议 VEGF 版本和功能的那操作能为肝的动脉或胆汁的树的损坏描绘的人的病理学的条件代表治疗学的策略。