Crohn's disease (CD) is a chronic remitting and relapsing disease. Fibrostenosing complications such as intestinal strictures, stenosis and ultimately obstruction are some of its most common long-term complications. Despite recent advances in the pathophysiological understanding of CD and a significant improvement of anti-inflammatory therapeutics, medical therapy for stricturing CD is still inadequate. No specific anti-fibrotic therapy exists and the incidence rate of strictures has essentially remained unchanged. Therefore, the current therapy of established fibrotic strictures comprises mainly endoscopic dilation as well as surgical approaches. However, these treatment options are associated with major complications as well as high recurrence rates. Thus, a specific anti-fibrotic therapy for CD is urgently needed. Importantly, there is now a growing body of evidence for prevention as well as effective medical treatment of fibrotic diseases of other organs such as the skin, lung, kidney and liver. In face of the similarity of molecular mechanisms of fibrogenesis across these organs, translation of therapeutic approaches from other fibrotic diseases to the intestine appears to be a promising treatment strategy. In particular transforming growth factor beta (TGF-β) neutralization, selective tyrosine kinase inhibitors, blockade of components of the renin-angiotensin system, IL-13 inhibitors and mammalian target of rapamycin (mTOR) inhibitors have emerged as potential drug candidates for anti-fibrotic therapy and may retard progression or even reverse established intestinal fibrosis. However, major challenges have to be overcome in the translation of novel anti-fibrotics into intestinal fibrosis therapy, such as the development of appropriate biomarkers that predict the development and accurately monitor therapeutic responses. Future clinical studies are a prerequisite to evaluate the optimal timing for anti-fibrotic treatment approaches, to elucidate the best routes of application, and to evaluate the potential of drug candidates to reach the ultimate goal: the prevention or reversal of established fibrosis and strictures in CD patients.
A comprehensive literature search was performed to assess all relevant citations found in Embase, Medline (service of the US National Library of Medicine (NLM) and the National Institutes of Health (NIH)) and the Cochrane Library for the following key words: ('Crohn's disease (CD') OR 'Crohn's' AND ('stricture' OR 'fibrosis'), ('kidney' OR 'liver' OR 'skin' OR 'lung' OR 'systemic nephrogenic' AND 'fibrosis' OR 'anti-fibrotic therapy'). Additionally, references of cited original articles and reviews were further assessed for relevant work. The search included studies between 1960 and 2013. These data together with the authors' personal experience in the field represent the basis of this review.
Crohn's disease (CD) is a chronic remitting and relapsing disease. During acute flares, CD patients may present with mainly inflammation driven symptoms such as diarrhea, abdominal pain and weight loss. However, over the long-term, the naturally progressive disease course often culminates in stricture formation. For example, around 40% of CD patients with ileal disease develop clinically apparent strictures. Strictures may be subdivided into fibrotic and inflammatory as well as mixed forms. Accordingly, strictures including inflammatory alterations might benefit from anti-inflammatory therapy through a reduction of the inflammation-mediated edema. During the last two decades, the therapeutic armamentarium for CD has expanded significantly, especially with the use of anti-tumor necrosis factor alpha (TNF-α)-based strategies that can lead to sustained clinical response rates in a substantial proportion of CD patients[6–8]. The success of anti-TNF antibodies fueled the hope for altering the natural course of CD. Most recent epidemiological data, however, revealed that despite the establishment of early immunosuppressive therapy in CD patients with an increased risk of disabling disease, the frequency of fibrostenosing complications did not significantly change. Thus, a specific anti-fibrotic therapy for stricturing complications in CD patients is needed. Despite recent advances in the pathophysiological understanding of intestinal fibrosis in CD[10, 11] and in contrast to fibrotic complications in other organs, no specific anti-fibrotic drugs for intestinal strictures are currently available, and all existing therapies used in clinically apparent CD-associated stenosis are the same that are prescribed for active luminal disease. The same holds true for the treatment of penetrating CD, another inflammatory bowel disease (IBD)-associated complication that is linked to impaired intestinal remodeling and healing. Available drugs for the treatment of fibrostenosing or penetrating IBD are depicted in Figure 1. Consequently, the therapy of choice for fibrostenosing CD, in conjunction with purely anti-inflammatory therapy, comprises endoscopic dilation (ED) procedures as well as surgical approaches, with all their associated limitations and morbidity[12–14]. A significant number of patients have to undergo multiple surgeries, with the subsequent risk of developing intestinal failure. In general, isolated strictures with a length of 4 cm or less which are devoid of ulcers and are accessible by colonoscopy or double-balloon enteroscopy qualify for ED. Although ED procedures for stricturing CD are usually technically successful, more than one third of patients will still undergo surgery within the next years due to insufficient response to ED[12–14]. In addition, major complications such as bowel perforation, bleeding or infection are reported in a range of 2 to 5%[12, 18]. In those CD patients where endoscopic stricture therapy is technically not feasible or not indicated, surgical approaches including resection and strictureplasty are recommended. While repeated surgical bowel resections bear the risk for induction of deficiencies in gastrointestinal functions and ultimately may manifest short bowel syndrome and intestinal failure, strictureplasty can treat intestinal obstruction without reducing intestinal length. Here, the incidence of major complications including anastomotic leakage, abscess, fistula or sepsis is present in about 6%. The recurrence rates differ between various forms of strictureplasty from 23 to 41%[20–22]. To date, no head to head comparison between ED and strictureplasty has been performed yet. Taken together, the insufficient therapeutic impact of currently available anti-inflammatory drugs on stricture prevention and treatment, the complications associated with ED or surgical treatment approaches associated with high socioeconomic burden as well as the high recurrence rates of stricturing CD after procedures demand the development and evaluation of specific anti-fibrotic agents for stricturing CD.
Therapeutic strategies to modify wound healing in Crohn's disease. Currently available therapies for stricturing or fistulizing CD are depicted. Data derived from Embase, Medline and ClinicalTrials.gov. 6-MP, 6-mercaptopurine; AZA, azathioprine; CD, Crohn's disease; ECM, extracellular matrix; IL, interleukin; mAb, monoclonal antibody; TNF, tumor necrosis factor.
Fibrosis is defined as the accumulation of collagen-rich extracellular matrix (ECM) in response to tissue damage and is a common complication of multiple chronic diseases. Repetitive or persistent injury of the intestinal epithelium and subsequently deeper layers of the intestinal wall may initiate, perpetuate or maintain progressive fibrosis. With regard to the gastrointestinal tract, acute, short-lived epithelial damage may occur as a consequence of peptic ulcers, infectious enteritis or mild diverticulitis, leading to a full restitution of tissue structure. In contrast, in CD, the gastrointestinal mucosa is exposed to chronic remitting or continuous pro-inflammatory and environmental stimuli. Pleiotropic mechanisms are activated like cellular stress, increased production of inflammatory cytokines and chemokines such as IL-13 or IL-17[25, 26] and growth factors, such as transforming growth factor beta 1 (TGF-β1), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). These mediators crucially contribute to morphological and functional alterations within the bowel wall that may finally culminate in stricture formation and loss of physiological gut functions[31, 32]. In the murine model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, inhibition of IL-13 signaling by administration of small interfering RNA targeting the IL-13-α2 receptor attenuated inflammation-associated intestinal fibrosis. This observation was corroborated by work from the same group, indicating that TGF-β1 secretion by macrophages was increased upon IL-13 stimulation in vitro and in vivo. Contractility of isolated intestinal smooth muscle from CD patients was enhanced after pre-stimulation with IL-13. Additionally, increased IL-13 transcripts were detected in muscle extracts from intestinal samples of fibrotic CD patients compared to samples from non-inflamed areas, which results in inhibition of fibroblast matrix metalloproteinase (MMP) synthesis. In contrary to these findings, there was no difference in IL-13 production in mucosal explants and lamina propria mononuclear cells between patients with stricturing CD and control subjects in a different study.
IL-17A was found to possess pro-fibrotic activity in various cell types including cardiac fibroblasts, hepatic stellate cells, skin fibroblasts and lung epithelial cells. In addition, IL-17E was shown to increase collagen production in lung fibroblasts. Consistent with a role of IL-17 in fibrosis IL-17 tissue levels were increased in a murine model of intestinal fibrosis. In human fibrotic CD, IL-17A, but not IL-17E, was overexpressed within tissue samples from CD strictures as compared to non-strictured CD areas and healthy gut. IL-17 secretion from cultured intestinal explants from strictured CD patients was significantly increased as compared to non-strictured CD samples. Moreover, myofibroblasts from CD strictures, expressing the IL-17A receptor, generated more collagen and tissue inhibitor of metalloproteinase 1 (TIMP-1) and revealed inhibitory effects on myofibroblast migration. In a clinical trial of patients with inflammatory CD, however, blockade of anti-IL-17A by administration of the anti-IL-17A antibody secukinumab failed to improve disease activity, was associated with a high rate of serious adverse events and had to be stopped prematurely since predefined criteria for futility were met, indicating that further studies are necessary before using anti-IL-17-based strategies in the therapy of intestinal fibrosis.
The core mediator in various organs for both, the initiation as well as the maintenance of fibrosis is TGF-β. This growth factor is produced by a vast majority of cells and organs in mammals and is stored in large amounts extracellularly through chemical cross-links to the ECM. The TGF-β/Smad signaling pathway appears pivotal for the development of fibrosis. Canonical intracellular signal transduction is mediated by Smad2/3 phosphorylation by TGF-β receptor I kinase leading to binding of Smad4. This complex translocates into the nucleus and induces TGF-β-specific pro-fibrotic gene expression. Inhibitory members of the Smad family such as Smad6/7 block the phosphorylation of Smad2/3 via competition with the TGF-β receptor I kinase[47, 48].
In addition to the above mentioned mediators, the imbalance of MMPs and TIMPs, which are physiologically involved in maintaining a state of 'healthy' remodeling and restitution, can aggravate structural changes of the bowel wall[48, 49].
Restoring the integrity of the intestinal barrier, culminating in epithelial wound closure may help to resolute and regress fibrosis, since continuous barrier defects appear to be one potential trigger for chronic inflammation promoting pro-fibrotic alterations. To this aim ECM-producing mesenchymal cells are recruited. These cells may migrate from neighboring tissue, originate from circulating mesenchymal cell precursors or bone marrow stem cell-derived mesenchymal cells, arise by proliferation from existing mesenchymal cells or result from epithelial- or endothelial-mesenchymal transition (EMT and EndoMT, respectively). Recently, the intestinal microbiota has been identified as a key pro-fibrotic factor, as suggested by several lines of evidence: 1) Ligands to Toll-like receptor 4 (TLR4) (predominantly from gram-negative bacteria) or TLR2 (predominantly from gram-positive bacteria) activate NF-κB, resulting in cytokine and chemokine secretion by intestinal mesenchymal cells. 2) In several experimental colitis models, microbes initiate or perpetuate gut inflammation and fibrosis, such as in SAMP1/YitFc mice, the IL-10 knock out mice, TNBS and peptidoglycan-polysaccharide (PG-PS)-induced colitis. 3) In humans, gene variants that affect innate immunity, located in or near genes involved in bacterial recognition and processing, are genetically associated to IBD or CD as well as complicated CD courses. 4) Finally, circulating antibodies against microbial components are commonly found in IBD patients and are believed to arise from an immune response towards the luminal microbiota. These antibodies are qualitatively and quantitatively associated with and predictive of a more complicated disease phenotype including fibrostenosis[50, 56–58].
Beside chronic inflammation as a major driver of intestinal fibrosis, inflammation-independent mechanisms deserve closer attention. In particular, activated mesenchymal cells, also referred to as disease-activated myofibroblasts, produce and secrete high levels of several collagen types, such as type I, III and V[59–61] and ECM compounds, such as fibronectin or tenascin C[62, 63] which get deposited, linked and subsequently form matrix networks that can lead to increased tissue stiffness. Stiffness in itself in the absence of inflammation activates further mesenchymal cells in the form of a positive feedback loop. The ability of myofibroblasts to contract might further increase the luminal narrowing of the intestine and contraction can be induced by factors other than inflammatory mediators. Interestingly, latent matrix-bound TGF-β1 can be activated by mesenchymal cells' traction forces, pulling against a mechanically resistant ECM. This leads to a conformation change of the latency-associated peptide liberating the active TGF-β1.
In summary, despite different physiological functions and unique features of the human gut, such as the high load of microbial components, intestinal fibrosis shares pathological core features with fibrosis of other organs, such as the lung, kidney, skin or liver. Consequently, anti-fibrotic agents with proven efficacy in fibrotic disease of these organs may represent promising candidates for stricturing CD and will be discussed in the following section.
Commonly used drugs for the anti-inflammatory therapy of CD have been observed to possess at least minor anti-fibrotic properties in other organs. For example, corticosteroids were found to decrease pro-collagen expression in vivo and in vitro as well as to inhibit collagenase activity. Corticosteroids show some effect in retroperitoneal fibrosis, systemic sclerosis and idiopathic pulmonary fibrosis (IPF). In contrast, human intestinal myofibroblasts respond to corticosteroids with enhanced pro-collagen expression upon dexamethasone stimulation. In stricturing CD, small case series report variable therapeutic success rates of intralesional steroid injection. The long-term systemic administration of corticosteroids in CD, however, is obsolete due to severe and pleiotropic side effects. Azathioprine, one of most commonly prescribed immunosuppressive drugs for maintenance of remission in CD patients, is beneficial in the treatment of retroperitoneal fibrosis and fibrotic pulmonary disease[75, 76]. In CD patients, azathioprine may delay postoperative, fibrotic complications, however, the early use of immunosuppressive treatment regimens does not reduce the occurrence of intestinal strictures and frequency of surgical interventions in the long-term[9, 78]. TNF-α is a critical cytokine in the pathogenesis of IBD and to date four anti-TNF antibodies have shown clinical efficacy as anti-inflammatory agents[79–82] and are available for clinical use. Several reports from liver fibrosis, pulmonary fibrosis and systemic sclerosis suggest an anti-fibrotic effect of anti-TNF treatment. This could be explained by TNF-α-mediated myofibroblast activation, increased collagen production and TIMP-1 expression as well as inhibition of MMP-2 activity and collagen degradation. In contrast, human intestinal myofibroblasts from CD patients show increased expression of TIMP-1 and decreased collagen production upon exposure to infliximab. After initially conflicting data in patients with CD with a possible pro-fibrotic effect of anti-TNF therapy in vivo, recent data revealed no link between anti-TNF administration with intestinal stricture formation. Information derived from a small retrospective study points towards at least a partial amelioration of stricture formation with anti-TNF therapy and anti-TNF treatment may delay the time to surgery in CD.
In daily clinical practice, most CD patients present with established strictures, representing the end-stage of the fibrotic process, and most clinicians see this scenario as an inevitable progression to a likely surgical intervention. This does not have to be so, as the theoretical and practical feasibility to stop or even reverse intestinal fibrosis is supported by the observation that tissue alterations in experimental models of intestinal fibrosis disappear after elimination of the pro-fibrotic stimulus. No therapeutic medical strategy for pre-existing intestinal strictures exists at the moment, but this clinical scenario could greatly improve by looking at existing knowledge derived from other organ systems.
Anti-fibrotic strategies used in the kidney, lung, liver, heart or skin can be grouped into strategies modulating growth factors, inflammation or oxidative stress, intracellular enzymes, and ECM production or assembly (Figure 2). We herein provide a summary of currently available experimental anti-fibrotics that have been tested for indications outside of the intestine. We selected promising mechanisms and agents that could be applicable to stricture therapy of CD in the near future and describe them in greater detail.
Pipeline for therapeutic strategies to alter and improve fibrosis in organs other than the intestine. Each color represents a particular organ. Agents are classified based on their mode of action. Data derived from Embase, Medline and ClinicalTrials.gov. CCL2, chemokine ligand 2; CTGF, connective tissue growth factor; ECM, extracellular matrix; HIF, hypoxia inducible factor; IL, interleukin; JAK, janus kinase; JNK, c-Jun N-terminal kinase; mAb, monoclonal antibody; SAP, serum amyloid P component; TGF-β, transforming growth factor beta; VIP, vasoactive intestinal peptide.
Feasibility of TGF-β1 blockade to treat fibrotic diseases has been shown in IPF. In this condition, TGF-β is driving fibrotic alterations and epithelium-dependent fibroblast activation. In murine models of IPF, antagonizing TGF-β action via Tβ-RII (as a ligand decoy), P144, an inhibitor of TGF-β activity, or P17, an anti-TGF-β peptide, resulted in potent anti-fibrotic effects[91–93]. In human IPF patients, two phase III trials have shown that treatment with pirfenidone, an agent inhibiting TGF-β activity and p38 mitogen-activated protein kinase (MAPK) signaling, improved pulmonary function[94, 95]. Pirfenidone is expected to be approved for IPF in Europe soon. Another example for the potential of anti-TGF-β-based strategies is scleroderma, a disease characterized by enhanced expression of TβRI and TβRII in fibroblasts leading to increased collagen I production and ECM deposition in the skin and internal organs. Topical treatment with P144 has shown efficacy in patients with systemic sclerosis, and multiple trials with this agent are currently ongoing. Fresolimumab (GC1008) is a humanized antibody targeting anti-TGF-β1,2 and 3 and was recently evaluated in a phase I trial in patients with treatment-resistant primary focal segmental glomerulosclerosis. The humanized αVβ6 integrin-blocking antibody STX-100, which inhibits the activation of latent TGF-β on epithelial cells, is currently being examined in a phase II trial in IPF patients[24, 99]. Comparable results have been reported from kidney fibrosis: preclinical in vitro and in vivo studies indicate an anti-fibrotic activity using anti-TGF-β antibodies, soluble TGF-β receptor, blockade of TGF-β activation by decorin, a small-molecule inhibitor of TGF-β receptors, administration of inhibitory protein Smad7 and thrombospondin-1 (THBS-1) blocking agent inhibiting TGF-β activation. In human patients with focal segmental glomerulosclerosis, a phase I trial with fresolimumab revealed promising results. Moreover, hepatic growth factor, acting as an inhibitor of Smad2/3 translocation in fibroblasts was observed to mediate anti-fibrotic effects in experimental models of renal and liver fibrosis but was also associated with an increased risk of hepatocellular carcinoma. Substrate specificity of therapeutics needs to be taken into consideration as well. In an experimental model of scleroderma, blocking activin receptor-like kinase 5 (ALK5), which is involved in phosphorylation of Smad2/3, leads to decreased fibroblast activation. However, ALK5 blockade in clinical trials was associated with adverse events due to cross-reactivity with other kinase inhibitors.
In addition to the Smad-signaling cascade, non-Smad pathways comprising TGF-β1 activated MAPKs and several tyrosine kinases have been targeted for anti-fibrotic actions. For example, c-Abelson (c-Abl), a component of the Bcr-Abl oncogene, can be effectively blocked by selective tyrosine kinase inhibitors such as imatinib. This agent inhibits PDGF as well and thus potentially regulates fibroblast proliferation and transformation. Despite promising results from in vitro and in vivo studies, to date limited experience with tyrosine kinases in human fibrotic diseases is available[107, 108]. Of note, novel tyrosine kinase inhibitors such as nilotinib and dasatinib mediate dose-dependent decreases in ECM production and reveal even greater efficacy as compared to that of imatinib, while being well tolerated by the patients. In contrast to TGF-β1, other members of the TGF family such as TGF-β3 possess anti-fibrotic properties. Avotermin is a recombinant bioactive human TGF-β3 that has been tested for treatment of dermal scars and significantly reduces the scar size by intradermal injection therapy. In addition, further growth factors such as serum amyloid P (SAP) have been proven effective in experimental models[112, 113] of fibrosis and have already entered phase I clinical trials in human patients.
The scientific rationale to target TGF-β signaling in stricturing CD comes from in vitro as well as in vivo observations. For example, intestinal TGF-β overexpression in mice leads to colonic fibrosis and obstruction, while disruption of the TGF-β/Smad signaling cascade protects animals from intestinal fibrosis. In human tissue samples from colonic CD strictures, TGF-β and its receptors as well as pSmad2/3 expression are increased, while Smad7 expression was significantly reduced. Although targeting TGF-β signaling for fibrotic diseases has a strong scientific rationale, it has to be taken into account that this growth factor is not only crucially involved in fibrogenesis but additionally functions as a key regulator of cellular processes including differentiation, proliferation, transformation, tumor suppression as well as immunoregulation and its actions may be context-dependent[96, 117]. For example, TGF-β1-deficient mice develop severe multiorgan inflammation and expire by 5 weeks of age[118, 119]. This outcome occurs even under germ-free conditions and is mediated by CD4+ T cells. Similarly, targeted deletion of Smad2 and Smad4 is associated with early death in mice[122, 123]. Furthermore, administration of metelimumab, a monoclonal antibody against TFG-β1, in human systemic sclerosis patients was associated with significantly more serious adverse events than placebo treatment including musculoskeletal pain, progression of skin involvement and death. Possible side effects during anti-TGF-β therapy would have to be carefully monitored, in particular in case of pre-existing inflammation. Therefore, neutralizing TGF-β 1 in vivo, as an anti-fibrotic approach in CD may be highly problematic, as this may actually lead to disease exacerbation given the potent anti-inflammatory and immunoregulatory properties of this cytokine.
HMG-CoA reductase inhibitors were developed with the intention to decrease cholesterol levels. More recently, they were found to mediate anti-inflammatory as well as anti-fibrotic effects in vitro, including decreased proliferation of mesangial cells, lower fibronectin as well as type IV collagen expression and decreased secretion of TGF-β1 and connective tissue growth factor (CTGF)[126–128]. Corroborating these in vitro findings, HMG-CoA reductase inhibitors revealed various anti-fibrotic effects in murine models of nephropathy and fibrosis[126, 127]. In CD patients, HMG-CoA reductase inhibitor atorvastatin was shown to mediate anti-inflammatory effects such as inhibition of T cell recruitment via reduced CXCL10 levels and reduce surrogate inflammatory markers such as calprotectin, C-reactive protein and TNF-α expression. Furthermore, it was demonstrated that simvastatin reduced TGF-β1 expression in human fibroblasts by inhibition of Smad3 phosphorylation leading, together with induced apoptosis in fibroblast and myofibroblasts, to a significant amelioration of experimental fibrosis. In addition, mesenchymal cells isolated from patients with radiation-induced intestinal fibrosis respond to pravastatin treatment with significantly decreased production of fibronectin and type-1 collagen through Rho-/ROCK-dependent reduction of CTGF expression. Nevertheless, the exact anti-fibrotic potential of statin treatment in stricturing CD still needs to be defined by the use of hard clinical endpoints, but this drug class has an already established safety profile for routine clinical use and could serve as a potential anti-fibrotic treatment approach.
Angiotensin II (AT II) is the major mediator of the renin-angiotensin system (RAS). AT II may increase ECM accumulation through plasminogen activator inhibitor-1-mediated decrease of MMPs and enhance TGF-β1 production in cardiac and renal fibrosis[134, 135]. The impact of AT II can also be observed in liver fibrosis. In hepatic stellate cells, AT II induces contraction and proliferation accompanied by increased collagen and TGF-β expression. Accordingly, progression of liver fibrosis in hepatitis C virus positive patients is significantly decreased after treatment with angiotensin-converting enzyme inhibitors. AT II is crucially involved in the manifestations of renal fibrosis by induction of pro-fibrotic effector molecules and EMT resulting in enhanced ECM production, and inhibition of AT II using angiotensin-converting enzyme (ACE) inhibitors or blocking agents towards the AT I receptor has emerged as a therapeutic approach to slow down renal disease progression and revealed anti-fibrotic actions in the lung, heart and liver[140–143]. Interestingly, all components of the RAS have been detected in the human colonic mucosa and AT II is increased in the mucosa of CD patients. In vivo administration of the ACE inhibitor enalaprilate has been proven to reduce weight loss and histological damage in murine dextran sulfate sodium (DSS)-induced colitis. ACE inhibitor treatment was also effective in spontaneous colitis of IL-10-deficient mice and this finding has been confirmed by other studies[148, 149].
Of note, through its AT1 receptor, AT II enhances the expression of CTGF, and administration of AT II inhibitors and AT1 receptor antagonists significantly ameliorates or reverses fibrotic alterations in experimental colitis reflected by reduced collagen amounts and TGF-β1 mRNA levels[150, 151]. Existing preclinical data in IBD combined with clinical trials from the liver and kidney make RAS modulation a promising future approach for CD-associated fibrosis.
Pro-inflammatory cytokines contributing to the pathogenesis of IBD could also be involved in the development of intestinal fibrosis in CD. For example, IL-1 modulates myofibroblast activation, chemokine production, MMP secretion and is involved in EMT induction. IL-6 is known to regulate TGF-β and TGF-βR2 expression as well as fibroblast proliferation[154, 155] and is strongly upregulated in serum and tissue samples from CD patients. IL-4 and IL-13 represent pivotal mediators of immune activation and T helper cell 2 responses are crucially involved in the development of intestinal fibrosis in vivo. IL-13 mediates, through binding to its IL-13Rα, an increased production of TGF-β and is a key player in the initiation of fibrotic alterations in the intestine. Confirmatively, antagonism of IL-13 is effective to prevent fibrosis development in experimental colitis[33, 157]. In addition, several IL-13 antibodies such as lebrikizumab, tralokinumab and QAX576 as well as the anti-TNF antibody etanercept and the immunomodulatory drug thalidomide are currently being evaluated for their anti-fibrotic potency in liver fibrosis and pulmonary fibrosis[24, 158–160].
The process of inflammation and fibrosis are likely to be intertwined through angiogenesis and lymphangiogenesis. Increased levels of factors implicated in angiogenesis have been documented in IBD patients, such as vascular endothelial growth factor A (VEGF-A). At a cellular level, PDGF increases proliferation and migration of fibroblasts and myofibroblasts. In the human intestine, PDGF facilitates ECM deposition and is upregulated in inflamed colonic tissue specimen of CD patients. Experience with blocking these agents in other fibrotic diseases exist. In a phase II trial, combined blockade of VEGF, PDGF and bFGF by the indolinone derivative BIBF 1120 tends to decrease the development of human IPF. Critical for the future use of inflammation modulators in the therapy of CD-associated fibrosis will be the quality, quantity and the timing of the approach because all of the above mediators act at different times throughout the disease course, in differing combinations and quantities. Additionally, all of the above molecules interact with each other and blocking a single cytokine at a specific time might not be sufficient for effective anti-fibrotic therapy.
The imbalance between deposition and degradation of ECM in fibrotic disease is a logical target for anti-fibrotic treatment approaches. Stimulation of MMPs as central regulators of ECM disassembly were expected to reverse fibrotic alterations, however, clinical studies in patients with nephrosclerosis failed to show efficacy. Likewise, depletion of TIMP should decrease fibrotic changes, but no amelioration of renal fibrosis was observed following TIMP inhibition in mice. With regard to the intestine, there is growing evidence for MMPs as a regulator of intestinal barrier function and mucosal defense, indicating pleiotropic functions of this molecular group in addition to purely matrix regulation. For example, serum MMP-9 levels correlate with disease activity in pediatric CD patients and may be used as a biomarker to follow the course of disease in adult CD patients as well[168, 169]. Colonic tissue expression of MMP-1, MMP-2, MMP-3 and MMP-9 was significantly increased in samples from inflamed mucosa as compared to non-inflamed mucosal samples. Increased MMP-9 expression in inflamed tissue colonic specimen from CD patients seems to be associated with decreased likelihood of disease recurrence. Finally, in mucosa specimen overlaying colonic strictures in CD patients, MMP-3 and MMP-12 expression was significantly reduced. Thus, MMPs need to be further and carefully investigated as possible targets for anti-fibrotic treatment in as well as outside of the intestine and are not yet ready for prime time.
The mammalian target of rapamycin (mTOR) protein is a serine/threonine protein kinase that consists of several complexes among which mTOR complex 1 regulates protein synthesis, proliferation as well as fibrotic actions. mTOR inhibitors possess direct anti-fibrotic properties by decreasing fibroblast and myofibroblast numbers and by reducing pro-fibrotic cytokine expression, including IL-4, IL-6, IL-13, IL-17, TGF-β1 as well as type I and III collagen[172, 173]. Efficacy of mTOR inhibitors have been demonstrated in numerous fibrotic disorders of the skin, lung, kidney and liver. With regard to CD, a randomized, double-blind clinical trial found that everolimus was as effective as azathioprine to achieve steroid-free remission in 138 patients with active CD. Additionally, there are two case reports indicating that mTOR inhibitors sirolimus and everolimus are able to induce remission in refractory CD[175, 176]. Given the fact that mTOR inhibitors possess anti-fibrotic as well as immunosuppressive effects, this class of drug appears to be promising for intestinal fibrosis therapy, however, the definitive therapeutic potential for intestinal fibrosis remains to be defined yet.
Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a nuclear receptor that modulates gene expression and is involved in various physiological and pathological processes including inflammation and fibrosis. After stimulation with specific ligands, PPAR-γ directly antagonizes Smad3 or reduces CTGF expression. PPAR-γ agonists are able to improve experimental fibrosis, while PPAR-γ selective antagonists abolish anti-fibrotic actions[179, 180]. Given the fact that CTGF is a key downstream effector of TGF-β on connective tissue cells, FG-3019, a humanized antibody targeting CTGF, has been developed and successfully passed phase I trials in several fibrotic disorders and recently entered phase II studies. In the human intestine, PPAR-γ has been detected in the colonic mucosa and has been identified as a mediator of established anti-inflammatory drugs such as 5-ASA[177, 181]. The future role of PPAR-γ agonists as a possible target for anti-fibrotic treatment in stricturing CD is promising, given the combined action against inflammation and fibrosis and its well-defined mechanism of action. Furthermore, other drug candidates such as endothelin A receptor antagonist bosentan have shown promising results in patients with IPF and renal interstitial fibrosis and deserves further investigation[182, 183].
A summary of compounds used as anti-fibrotic therapies in other organs and their mode of action is depicted in Figure 3. Anti-fibrotic clinical trials of major interest are shown in Table 1.
Compounds used as anti-fibrotic therapies in other organs and their mode of action. The blue boxes represent a major profibrotic pathway. Compounds are depicted in red, indicating their mechanism of action. Abs, antibodies; ALK, activin receptor-like kinase; AT, angiotensin; CTGF, connective tissue growth factor; ECM, extracellular matrix; HGF, hepatocyte growth factor; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; Inh, Inhibitor; IL, interleukin; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PPAR, peroxisome proliferator-activated receptor; SMAD, small mothers against decapentaplegic; TGF, transforming growth factor.
AT1, angiotensin II receptor antagonist subtype 1; CXCL, CXC ligand; ECM, extracellular matrix; FVC, forced vital capacity; IL, interleukin; IPF, idiopathic pulmonary fibrosis; RCT, randomized controlled trial; SAP, serum amyloid P component; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor.
The most efficient anti-fibrotic treatment approach still remains the elimination of the primary cause of intestinal injury, which would mean nothing less than curing CD. However, since a magic bullet for CD is not and will most likely not be available in the near future, clinical evaluation and optimization of anti-fibrotic drug candidates for stricturing CD is a justifiable and promising treatment strategy.
However, the simple transfer of these agents into CD treatment is premature and multiple obstacles have to be overcome to make use of the above described mediators and mechanisms.
First, the ideal anti-fibrotic drug should target something uniquely expressed in a specific fibrotic complication in a particular organ and should not display any systemic side effects. This is particularly true in case of concomitant injury elsewhere in the body. To date, however, no specific target for intestinal fibrosis or other fibrotic disease has been identified, which supports the hypothesis that mechanisms of fibrosis are shared between different organs.
Second, the optimal timing to commence anti-fibrotic treatment is of utmost importance to CD patients, however, is not defined yet. It is obvious that an early use of anti-fibrotics is expected to be associated with a better outcome in patients prone to this complication. Pre-existing fibrosis and concomitantly increased tissue stiffness can perpetuate fibrosis even in the absence of inflammation. Data from experimental fibrosis seems to confirm that there might be a critical point in evolution of fibrosis when the progress becomes irreversible. Therefore, an early treatment with anti-fibrotics at the same time of anti-inflammatory agents might be mandatory in human CD patients. Unique to CD is a fistulizing disease process and this complication needs to be kept in mind when using drugs inhibiting tissue remodeling because this could theoretically promote fistulizing disease. However, timing may not be simply based on the disease duration, since up to 50% of CD patients present with stricturing or penetrating disease at the time of first diagnosis.
Third, a patient-tailored anti-fibrotic treatment approach necessitates the identification of biomarkers to enable individual risk stratifications for stricturing disease and to follow the individual evolution of fibrosis. As opposed to other organs, such as liver[187, 188] or lung, regrettably, no clinically useful biomarkers for stricturing CD as well as for assessment of therapeutic response are available yet. Promising approaches include serology[189, 190] or imaging techniques[191–196], but the currently used tools only detect endpoints based on clinical findings of possible CD fibrosis and hence are not accurate.
Fourth, the best route of application for anti-fibrotic agents in stricturing CD has to be elucidated. In line with the beneficial effects of systemic administration of anti-fibrotics in other organs, intravenous or oral application may be appropriate. The CD intestine offers the advantage of potential local therapy as a large proportion of strictures is accessible via endoscopy. Intralesional injection or topical application of anti-fibrotics is a valid and practical therapeutic option, as shown by steroid or infliximab application. This approach may be associated with fewer side effects as compared to systemic administration.
Finally, a general limitation to evaluating potential anti-fibrotic agents is the long-lasting evolution of fibrotic complications in patients with CD requiring clinical trials of long duration and large patient populations, making them very expensive and impractical.
It is unclear and in the realm of speculation, which of the reviewed drugs has the highest potential for success as an anti-fibrotic treatment in CD. Combining drugs with a known safety profile and anti-fibrotic efficacy, such as HMG-CoA reductase inhibitors, mTOR inhibitors or inhibitors of the angiotensin system, could serve as a starting point. Given the effect of most substances on a reduction of TGF-β1 proper precaution needs to be taken for carefully monitoring intestinal inflammation. Novel drug delivery systems, such as the Multi Matrix System (MMX®), allowing oral administration of a compound with the substance being released in a defined area of the gastrointestinal tract (such as the terminal ileum) can circumvent systemic side effects, such as hypotension for angiotensin blockade.
To move forward with specific anti-fibrotic therapies in the future we need to focus on identifying mechanisms of fibrogenesis and to develop new and better animal models for this disease (Figure 4). What, however, is badly missing is the availability of biomarkers for natural history and response to therapy that are readily available and easy to measure. Only through utilization of these markers will the field be able to design clinical studies of reasonable length and sufficient patient number, reflected in affordable budgets that put our ability for testing anti-fibrotic therapies within reach.
A suggested path to more efficient translation of new discoveries to Crohn's disease-associated fibrosis. Adapted from Friedman et al.. IBD, inflammatory bowel disease.
Stricturing CD is still an unresolved problem with strong implications for the patients and a high socioeconomic burden due to frequent hospitalizations and surgery. Despite recent advances in the pathophysiological understanding of fibrosis and significant expansion of the anti-inflammatory armamentarium over the last few decades, the occurrence of intestinal strictures in CD patients did not significantly change. To date, effective therapeutic approaches for stricturing CD are limited to ED or surgical interventions. The data presented in this review highlight the pleiotropic anti-fibrotic actions that have been observed with the use of numerous agents in fibrotic complications of the skin, the lung and the kidney. Thus, it is justified to propose further evaluation of these drug candidates in clinical trials for the management of intestinal fibrosis. However, previous establishment of non-invasive biomarkers to assess the degree of fibrosis, to monitor fibrotic evolution and to predict therapeutic response, combined with the development of imaging techniques to quantify intestinal fibrosis, appear to be essential pre-requisites for individual risk stratification and proper design of clinical trials.
Dominik Bettenworth and Florian Rieder contributed equally to this work.
DB was supported by a research fellowship from the Faculty of Medicine, University of Münster, Münster, Germany. FR is funded by the NIH (grant: 1T32DK083251-01A1). The authors would like to thank Dr Claudio Fiocchi and Dr Bo Shen, Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA, for helpful comments.
DB and FR developed the review concept, performed the literature review and wrote the manuscript. Both authors read and approved the final version of the manuscript.


You do not have to be a member of the Friends of Nockamixon State Park to volunteer for any of the many on-going projects. However, it is required that all volunteers complete the Conservation Volunteer Application Form at the Pennsylvania Department of Conservation and Natural Resources (DCNR) website. Please indicate Nockamixon State Park under "State Park Locations." Approval may take a few weeks so please try and plan to complete this form as soon as you are thinking of volunteering.


- la vraie mm si la situation economique au Portugal ne se prete pas trop a ce genre de lancement en ce moment !
C'est confirmé avec 5 nouvelles lignes.
easyJet today confirmed that it will open its 23rd base in Lisbon, with destinations appealing to both to business and leisure passengers. The initial operations will commence with five new services, Copenhagen, Amsterdam, Bordeaux and Venice and a brand new destination – Asturias, in addition to its 16 existing routes.
Travellers will now have a wider range of choices, with 21 routes from Lisbon and over 150 flights per week during the peak season.
As part of easyJet's aim to make travel easier, we will offer more frequencies and early morning departures, which will enable Portuguese business travellers to take return trips within the same day to key European cities such as Amsterdam and Copenhagen.
Initially easyJet expects to carry 225,000 additional passengers in the first year, with an additional two A319 aircraft that will be permanently based in Lisbon.
As part of its commitment to establish a base in Lisbon, easyJet will be recruiting around 100 employees for the base, the majority of which will be cabin crew and pilots. These additional flights will create further indirect jobs in various areas, from ground handling at the airport to the tourism industry.
"We are delighted to be confirming easyJet's new base in Lisbon. It illustrates our long-term commitment to the market and it will enable us to grow our operations further. Along with significantly contributing to the local economy, our new base will also boost visitors to Lisbon - with over 2 million passengers travelling to and from Lisbon, and 4 million in and out of Portugal in the first year, all travelling with easyJet."
Il n'y en a jamais pour MRS avec EZY. C'est désespérant.
Sebo a écrit: Il n'y en a jamais pour MRS avec EZY. C'est désespérant.


Average Height	: 13" - 15"
Average Weight	: 18 - 30 lbs.
The origin of the Beagle is uncertain. It's thought that it may have been derived from the French word begueule, meaning open throat, or from the Old English word 'beag' ~ meaning small. Another theory is that they think it may have come from the French word beugler, meaning to bellow, or the German word begele, meaning to scold.
While the Beagle history is somewhat cloudy ~ Greek documents from 400 B.C. describe Beagle-like dogs, and the Romans may have brought small rabbit-hunting hounds with them to England and bred them with the local hounds.
During the reigns of Edward II (1307 - 1327) and Henry VII (1485 - 1509), extremely small beagles, called Glove Beagles became popular in England.
They reportedly were small enough to be held in a gloved hand. There's also mention of Singing Beagles, named for their bugling voices. Today some breeders have attempted to breed a smaller version of Beagles known as "Pocket Beagles".
English hunters would take packs of these dogs out on the hunt tracking rabbits, hare, pheasant, quail and other small animals. The breed probably originated as a cross between the Harrier and other types of English hounds.
Elizabeth I (1533 - 1603) kept packs of Pocket Beagles that stood only 9 inches tall. These small dogs were depicted in paintings as short-legged and pointy nosed. They were used for hunting, but quickly fell out of favor because they weren't very fast.
In the 1700s, fox hunting became popular in England, and the Beagle fell out of favor as the larger Foxhound became the dog of choice. If it hadn't been for the farmers in England, Ireland, and Wales who continued to keep packs to hunt rabbit and hare, the breed might have become extinct at that time.
In the mid-1800s Reverend Phillip Honeywood established a pack of Beagles in Essex, England. These dogs are thought to be the ancestors of the modern Beagle. Rev. Honeywood bred for hunting skills, not looks. Thomas Johnson, a fellow Englishman, was responsible for breeding Beagles who were both attractive and good hunters.
Of interest is the "Patch" Beagle strain developed by Willet Randall in New York around 1880. The line is primarily white with a very large tri-colored spot. They were very popular in the 1940s and 1950s because they were able to run so fast. Today, many people call lemon and white or red and white beagles "Patch" beagles.
The American Kennel Club and the first Beagle specialty club both were founded in 1884.
Today.........Beagles have become one of the most popular breeds in the USA.
Beagles are known to hunt alone, as well as in pairs or in packs.
In 1916, 5members of the National Beagle Club purchased 508 acres in Western Loudoun County, Virginia, to hold field trials. They formed a corporation called 'Institute Corporate' to purchase, own then lease it to the Institute Foundation ~ that today continues to maintain the property for the National Beagle Club, where many activities of the National Beagle Club are held.
•	Active, outgoing, fun loving but also can be stubborn.
•	Require patient, creative, consistent training.
•	As a pack dog ~ Beagles get along well with other animals and their human friends.
•	"Beagle Brigade": As a scenthound ~ with an amazing sense of smell ~ Beagles are regularly used, for drug & contraband sniffing at airport baggage claim areas [22 USA International airports to date].
•	Do well in apartments.
•	Can suffer from separation anxiety, and destructiveness, if left alone for long periods.
•	Can be difficult to housetrain. Crate training is recommended.
•	Leaving in the back yard is also not recommended: digging, escaping, howling will ensue.
•	They are a popular breed in research laboratories, so they are often stolen/kidnapped. Make sure you have them 'micro-chipped'.
•	Can be independant. Love food ~ hence the nick name 'chow hound'. *Beagles can become very protective of their food.
•	Not the best protection or guard dog ~ just too friendly to everyone they meet.
•	Have a smooth, dense double coat that is resistant to rain. Need weekly brushing.
•	Known for ear infections.


A year after the Brihanmumbai Municipal Corporation (BMC) inaugurated a cycle parking area outside Mahim railway station, the facility is yet to be used by many. "In the past one year, I have hardly ever seen a cycle parked there. The area is often occupied by street dwellers who sleep under the shed," said a railway official at Mahim station.
"The area has always been inhabited by homeless people. The cycle stand was not going to change anything. In the past year, we have rarely seen any cycle here. Instead, the stand's shed has invited more people to sit under it," said Ramesh Kumar who runs a sugarcane juice shop nearby. Conceding that there are issues with the facility, the civic body still believes that the cycle stand that was inaugurated in January 2017 is serving its purpose.
"Like other parts of the city, here, too, we have a problem with street dwellers. During the monsoon, they come to take shelter here (under the shed). But our officials go on rounds and ensure that the area is cleared. However, the stand has received a good response and many people are using it to park their cycles. We started it to promote the habit (of cycling) as it is good for the environment. More awareness is needed to make it (cycling) more popular," said Ramakant Biradar, the Assistant Municipal Commissioner, G North ward.
ensure safety. "While we need cycle stands in the city, cyclists should feel secure about leaving their cycles there. Most cyclists in the city today own expensive cycles. If they have to leave those at the station and go to work, they should be assured that nobody will tamper with the cycles," said Sachin Wadekar, who cycles to work from Kandivalli to Andheri.
Rama Bishnoi, a Santacruz resident and a cyclist, said: "They should have started the initiative from a more crowded station like Bandra or Andheri. More people are likely to park their cycles there. Once that became popular, then they could have it at more stations.


text:
Ibn Abi Usaybi'a (en arabe ابن أبي أصيبعة موفق الدين أبو العباس أحمد بن القاسم بن خليفة الشعري الخزرجي, né à Damas entre 1194 et 1203, mort en 1269 ou en 1270) est un médecin historien, connu pour ses bio-bibliographies de grands médecins.

Biographie

Né dans une famille de médecins de Damas, il fait des études de médecine dans cette ville auprès de Al-Dakhwar, en étant le condisciple de Ibn al-Nafis.

Il se fait remarquer par ses contemporains comme oculiste pratiquant à l'hôpital Al-Nuri de Damas. Il entre au service de l'émir Azeddin à Sarkar, pour prendre ensuite la direction d'hôpitaux tant au Caire qu'à Damas.

Il travaille en collaboration avec Ibn al-Baytar de Malaga, pour l'étude et le classement des plantes médicinales. Il est aussi en correspondance avec Abd Al-Natif.

Œuvres
Polyglotte, Ibn Abi Usaybia traduisit en arabe le Sushruta Samhita, manuscrit de chirurgie rédigé en sanskrit et attribué à Sushruta, chirurgien indien du  avant notre ère.

Il serait également l'auteur d'une compilation d'observations médicales, aujourd'hui perdue.

Vies de médecins

Son ouvrage le plus important est un recueil de près de 400 biographies de médecins et scientifiques, le Uyūn al-anbā' fī ṭabaqāt al-aṭibbā (en arabe عيون الأنباء في طبقات الأطباء, littéralement Vies de médecins  ou Sources d'informations sur les classes de médecins.

Si plus de 380 de ces biographies sont consacrées à des médecins, d'autres concernent des mathématiciens, physiciens, astronomes ou encore des philosophes. Il écrivit cette compilation à Damas en 1242, avant qu'elle ne soit publiée en 1245 ou 1246.

L'ouvrage est divisé en quinze chapitres : 1. Origines de la médecine ; 2. Premiers médecins ; 3. Médecins grecs ; 4. Hippocrate et ses contemporains ; 5. Galien et ses contemporains ; 6. Médecins d'Alexandrie ; 7. Médecins du temps du Prophète ; 8. Médecins de Syrie sous les premiers Abbassides 9. Les traducteurs ; 10 à 15. Les médecins des autres régions du monde : Irak, Perse, Inde, Maghreb et Espagne, Égypte, Syrie.

Ce livre inaugure un nouveau genre médico-historique : les bio-bibliographies de grands médecins. Sa méthode est distincte de l'hagiographie (exemplarité et mise en valeur), Ibn Abi Usaybi'a ne s'intéresse à la vie des savants que pour mieux connaitre leur doctrine et cataloguer leurs œuvres. C'est aussi la première étude médico-historique à visée universelle, englobant tous les médecins illustres de l'ensemble du monde connu, et de toutes les époques.

L'ouvrage ne mentionne pas son compagnon d'études Ibn al-Nafis, malgré deux chapitres consacrés à ses contemporains en Syrie et en Égypte. Une rivalité, voire une inimitié personnelle, aurait existé entre les deux hommes.

En médecine européenne, cette approche biographique systématique débute avec les humanistes du , dont .

Supernova ayant donné naissance à la nébuleuse du crabe

L'œuvre historique d'Ibn Abi Usaybi'a est vaste et appréciée pour la richesse et la précision des extraits cités<ref name=":3">{{Commentaire biblio|dans Histoire de la pensée médicale en Occident, vol. 1, Antiquité et Moyen Âge, Mirko D. Grmek (dir.).}}</ref>. Nous lui devons ainsi une observation de la supernova de 1054  (SN 1054) qui donna naissance à la nébuleuse du crabe.

Dans sa biographie d'Ibn Butlan, ce dernier est le témoin d'une épidémie à Constantinople en 1054. Il la relie à l'apparition d'une nouvelle étoile dans la constellation des Gémeaux et à l'entrée de Saturne dans la maison du Cancer :

 Bibliographie
 .

  Le même, dans sa traduction allemande par August Müller, Königsberg, 1884.
 Ibn Abï Usaybi'a, Sources d'informations sur les classes de médecins,'' traduction française partielle H. Jahier et A. Noureddine, Alger, 1958.

Notes et références

Voir aussi
 Histoire de la médecine
 Médecine arabe au Moyen Âge

Historien de la médecine
Médecin arabe du XIIIe siècle
Médecin arabo-musulman
Naissance à Damas
Date de décès non renseignée (XIIIe siècle)
Personnalité syrienne du XIIIe siècle
Écrivain de langue arabe au XIIIe siècle

redpajama_set_name: RedPajamaWikipedia


text:
European Athletics U20 Championships
Duplantis surpasses championship record for pole vault gold
Armand Duplantis cleared 5.65m to break the championship record at the European Athletics U20 Championships in Grosseto
A day after the longest standing men's championship record was beaten with a 2.33m clearance in the high jump, Sweden's Armand Duplantis broke another long standing record to claim the pole vault title on the final day of the European Athletics U20 Championships in Grosseto, Italy.
Duplantis' performance was an art in economy as he ensured the gold medal with just his second jump of the competition by going clear at 5.55m on his first attempt. He then put the bar up to 5.65m and after two unconvincing efforts, Duplantis soared over the bar on his third attempt to break Maksim Tarasov's championship record of 5.60m set in 1989 before attempting 5.80m
Armand Duplantis just misses out on 5.80m but he wins the European U20 title with a championship record of 5.65m! #Grosseto2017 pic.twitter.com/h1xliiZbSD
— European Athletics (@EuroAthletics) July 23, 2017
Germany's Bo Kanda Lita Baehre cleared 5.45m to secure the silver medal and France's Romain Gavillon improved his lifetime best to 5.35m to claim bronze. "My season is over now, I'll rest a bit and then trainings for the winter will begin," said the Frenchman.
But for Duplantis, his season is far from over. The 17-year-old, who is still ranked third on the world lists with a world U20 record of 5.90m, will head to the World Championships in London next month where he is aiming to claim a medal.
Two out of three titles for Ingebrigtsen
Jakob Ingebrigtsen only made his debut at the 3000m steeplechase three weekends ago but the 16-year-old has already broken the long-standing European U20 record, qualified for the World Championships in London and now he has the continental title to his name.
Ingebrigtsen, who is also eligible for the next edition of this championships, was the fastest on paper by more than 10 seconds and despite sustaining some cuts and bruises from his fall in the 1500m final on Saturday evening, there was still plenty in the legs as the youngest athlete in the field coasted to his second title of the championships in 8:50.00.
Jakob Ingebrigtsen "hasn't trained for the steeplechase" but he added the European U20 title to his European U20 record. pic.twitter.com/ZLL39EcvMZ
Giger clocks 55.90 for 400m hurdles gold
Yasmin Giger coasted to a comfortable semifinal win but she had to battle all the way to reel in pre-race favourite Agata Zupin from Slovenia. Giger holds the Swiss U20 record on the flat and she used that flat speed to come through on the outside to claim the title and decimate her lifetime best in the process.
Giger's pre-race lifetime best stood at 57.42 but the 17-year-old bypassed the 56-second mark altogether, stopping the clock at 55.90 to move to sixth on the European all-time U20 lists - missing Zuzana Hejnova's championship record by just one-hundredth.
"I didn't expect to win the gold today but I had to be cool and just run till the end of the race. The atmosphere really helped because when you hear the crowd cheers for you, you can only go faster," said Giger.
Zupin also broke the 56-second barrier for the first time in her career, setting an outright national record of 55.96 to move to eighth on the European all-time U20 lists. Last year's European U18 champion Viivi Lehikoinen from Finland also took more than a second off her lifetime best, improving from 57.65 to 56.49 to win bronze.
Alessandro Sibilio came through late in the semifinal but dead last at the halfway point, the Italian had too much of a deficit to make up in the final as France's Wilfried Happio claimed gold in a national U20 record of 49.93. Sibilio made a late charge to claim silver in 50.34 - nearly two seconds faster than his pre-championships lifetime best - with David Jose Pineda third in a Spanish U20 record of 50.41.
GOLD FOR FRANCE!
Wilfried Happio wins gold in a national U20 record and European U20 lead of 49.93. #Grosseto2017 pic.twitter.com/82aYr3aY3o
Lamou shatters triple jump lifetime best
France also claimed the triple jump title as expected but the source of the title was a surprise. World indoor U20 record-holder Melvin Raffin had to settle for bronze with 16.82m behind 17-year-old Andrea Dallavalle from Italy (16.87m) and Martin Lamou, who improved his lifetime best from 16.34m to a European U20 lead of 16.97m in the second round.
Having won world U18 and world U20 titles in the last two seasons, Czech Republic's Michaela Hruba capped her stellar junior career by clearing 1.93m in the high jump before three attempts at a championship record of 1.96m which would have added one centimetre to a mark jointly held by Yelena Yelesina and Mariya Kuchina.
There was an upset in the 800m final as Croatia's Marino Bloudek fended off European U20 leader Markhim Lonsdale, 1:48.70 to 1:48.82 while Jemma Reekie put her fourth place finish in yesterday's 3000m final behind her by claiming the 1500m title in 4:13.25. In the 5000m, the Netherlands' Jasmijn Lau won gold in 16:38.85.
Serbia has another star in the making as Milica Gardasevic followed in Ivana Spanovic's footsteps by winning the long jump title with 6.46m while Poland's Oskar Stachnik won the discus title with a season's best of 62.01m.
Duplantis Armand
Ingebrigtsen Jakob
Giger Yasmin
Happio Wilfried
Lamou Martin
18-21 JULY
Implements List

redpajama_set_name: RedPajamaCommonCrawl


If you are facing charges for a violent crime, it is imperative that you retain immediate representation. Do not face the complexities of the legal system alone. Without the assistance of our criminal defense lawyer, you may find it difficult to obtain the outcome you desire.
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text:
La Symphonie pour orgue   « Gothique » est une œuvre de Charles-Marie Widor composée en 1895.

Cette symphonie pour orgue tire en grande partie sa substance thématique de l'hymne de Noël Puer Natus est, qu'elle paraphrase. Elle est dédiée à l'abbatiale Saint-Ouen de Rouen, dotée d'un grand orgue installé par Cavaillé-Coll en 1890. La « Gothique » fut suscitée par cet instrument nouveau, doté de quatre claviers et de 64 jeux, que Widor a lui-même inauguré et qu'il a qualifié admirativement de « alla Michel-Ange ».

Structure
 Moderato
 Andante sostenuto
 Allegro
 Finale (Moderato - Allegro - Moderato - Andante - Allegro)

Discographie
 Les dix symphonies de Widor, enregistrées par Pierre Pincemaille sur dix orgues Cavaillé-Coll. La  « Gothique »  en ut mineur est enregistrée sur l'orgue de l'abbaye Saint-Ouen de Rouen, le  (Solstice SOCD 185).

Références

Liens externes
 YouTube La Symphonie Gothique, avec la partition.
 Orgues en France L'orgue de l'abbatiale de St-Ouen de Rouen.

Œuvre de Charles-Marie Widor
Widor


i posted this days ago but now we invesigated a bit around so i try to repost.
we have 2 environments , nw2004s and r/3, we want in nw2004s to have a searchhelp called DEBI (the one of r/3), but how can this be achieved without having to rebuild the searchhelp in nw2004s (as DEBI is only in an erp-environment available) - DEBI just as a sample.
All guys how use WD JAVA must have the same "problems" i guess.
any hints would be very welcome!!!!
Since neither the data nor the data structures are available in the raw nw2004s system, you've got to recreate the search help and use rfc or copied data to access the content. Besides reusing the build-in DDIC search helps, Web Dynpro also offers the possibility to define your own search help and to create your own coding for retrieving the data from the other system at runtime (in case you don't want to copy it). Those search helps are called OVS. There should be some examples available in the system.


With all the parties and festivities expected before and during the Christmas period,you may have more than a usual need to keep in shape, relax or simply find time for yourself.
We are offering you the opportunity to receive 12 consecutive days of health, fitness and leisure to sample the Marriott experience.
To take advantage of this offer simply call us today.
*12 Days of Fitness may not be running at all Marriott leisure clubs, please check you club club offer click here Offer only applicable during November & December 2010. Promotional offer excludes Hanbury Manor. If you decide to join, monthly membership fees will apply. Promotion only available at participating Marriott Leisure Clubs (see MarriottLeisure.co.uk for details). All offers subject to availability. Terms and conditions apply. Facilities may vary from club to club.


The ill-timed speech has revitalised the fortunes of the pro-independence party.
Pro-independence forces have been rattled by their surprise loss in the 'midterm' local elections.
With a lot of players and not much time, concluding negotiations by 2021 is an ambitious goal.
Declining relations between Beijing and Washington signal turbulent times ahead for the Indo-Pacific.
Tokyo's strong ties to Washington may be jeopardised by the threat of auto tariffs.


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text:
UIL Football State Championships
December 17, 2021 | 11:00 AM
The 2021 Football State Championships come to AT&T Stadium for four days, starting on Wednesday, December 15th. Tickets will go on sale in early November.
Tickets are on sale now at SeatGeek.com.
11:00 AM, 1A Six-Man Division I
2:00 PM, 1A Six-Man Division II
7:00 PM, 2A Division I
11:00 AM, 2A Division II
7:00 PM, 3A Division II
11:00 AM, 4A Division I


REST API Modular Input: Why is the add-on not working correctly with Splunk 6.5.2?
Hi I have installed REST API Modular Input add-on on my Search Head. I am not seeing REST input under my data inputs.
I am using Splunk 6.5.2 version .
settings --> datainputs --> not seeing REST as per the documentation .
The functionality of the input works perfectly fine.
To be more specific, If you have REST + DBX on your machine you might face this issue of inputs not showing up.
Splunk DB Connect: How to pull data from sql server to Splunk indexer?
Has anyone successfully setup Splunk to ingest SNMP v3 traps using net-snmp?


text:
Q: mySQL - Selecting all records where all columns are unique Let's say I have a table like this
id  col1  col2  col3  col4  col5  col6
1    1     2     3     4     5     6
2    2     1     4     3     6     5
3    1     1     2     3     4     5

I would want to select the rows where every field has a different value. The out put would be
id  col1  col2  col3  col4  col5  col6
1    1     2     3     4     5     6
2    2     1     4     3     6     5

I know you can do this
SELECT * FROM table
WHERE col1 <> col2 AND col2 <> col3...

but that would take forever with this many columns. Is there a specific function for determining if all columns are unique?

A: You can unpivot your table using UNION ALL:
SELECT id
FROM (
  SELECT id, col1 AS col
  FROM mytable

  UNION ALL

  SELECT id, col2
  FROM mytable

  UNION ALL

  SELECT id, col3
  FROM mytable

  UNION ALL

  SELECT id, col4
  FROM mytable

  UNION ALL

  SELECT id, col5
  FROM mytable

  UNION ALL

  SELECT id, col6
  FROM mytable) AS t
GROUP BY id
HAVING COUNT(DISTINCT col) = 6

If you want all columns selected then you do something like:
SELECT *
FROM mytable
WHERE id IN ( .... above query here ...)

Unfortunately MySQL does not have an UNPIVOT operator that would make the above query less verbose.

A: A little less verbose than your solution, although it doesn't scale perfectly if the number of columns is excessively large:
SELECT
    *    -- In actual live code you would of course never use '*'
FROM
    MyTable
WHERE
    col1 NOT IN (col2, col3, col4, col5, col6) AND
    col2 NOT IN (col3, col4, col5, col6) AND
    col3 NOT IN (col4, col5, col6) AND
    col4 NOT IN (col5, col6) AND
    col5 NOT IN (col6)    -- Done as an IN just to be consistent

A: Try this i hope this will helping you
select
(SELECT group_concat(DISTINCT col1) FROM table) as col1,
(SELECT group_concat(DISTINCT col2) FROM table) as col2,
(SELECT group_concat(DISTINCT col3) FROM table) as col3,
(SELECT group_concat(DISTINCT col4) FROM table) as col4

redpajama_set_name: RedPajamaStackExchange


MBFWA ends with local rising stars, seasoned international talent and the toasting of a new magazine.
Friday marked the conclusion of MBFWA. Looking back, it was a week that encompassed a few key themes: geometric lines, vibrant prints, lace and lots of white. All up it was a surprisingly strong and commercially viable week. Easton Pearson and Karla Spetic were standouts, the festival's new home at Carriageworks was a success and numerous labels – Michael Lo Sordo, Vanishing Elephant, Emma Mulholland and countless others – came into their own and asserted themselves as no longer just emerging talents, but leading designers in their own right.
Designers aspiring to follow such a path were grouped together at the New Generation show. A proverbial goldmine, this year's show unearthed an array of impressive young designers. Betty Tran proved herself to be one to watch thanks to her use of sumptuous metallic brocades.
Building upon his interior design background, Jamie Ashkar, impressed with his construction, proportions and plunging necklines.
Interestingly, the group show also included a familiar name in Desert Designs. Originally a label from the 1980s, Desert Designs has recently undergone a revamp thanks to Jedda Daisy-Culley and Caroline Sundt-Wels, who next summer will ensure you'll want to walk along the Australian beach in vibrant Indigenous art prints. Red-carpet friendly designer Tristan Melle also caught everyone's eye, sending out an accessible and revealing collection that will no doubt appeal to Sydney's bronzed fashion set. His pairing of leopard print with lemon sorbet showed his undoubtedly original perspective, which we are sure to see more of.
An original perspective was also at the forefront of the Zambesi show. While local designers had ruled the catwalk all week, it was ironically the international label that closed MBFWA, and you could tell. Following a week of bright prints, body-con silhouettes and sheer cut-outs, the New Zealand label asserted its international approach with a collection that played on shade, proportion and trans-seasonal dressing. Elisabeth Findlay and Dayne Johnston focused on high necklines, tartan and little colour, while the menswear line was equally directional with experimental suiting and even a pair of overalls.
Once the official shows were over, the fashion set headed off to let their hair down. This year, the party on everyone's lips was the Hello Elle runway event, heralding the official introduction of Elle magazine to our shores. After rumours last year that the magazine was set to be relaunched, the Bauer Media group made the move, halting the production of Grazia and Madison in order to make way for the glossy Elle publication. Set to officially launch in September, the magazine will be helmed by Justine Cullen, previously of Shop Til You Drop magazine.


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Home eBooks Research & Innovation eBooks Page 2
Research & Innovation eBooks
DTU – Small is beautiful
This compelling document focuses on attention to detail, hence its apt title, 'small is beautiful'. This intriguing e-book is all about nanoscale imaging research and within that, the fascinating field of electron microscopy
Endocrine Disrupters: To Assess Or Not To Assess?
Endocrine Disrupting Chemicals (EDC) are chemical substances that can damage our health and/or the health of environmental organisms by altering the hormone function.
Boosting innovation in the wood technology sector
Professor Frédéric Pichelin from Bern University of Applied Sciences takes us on a journey to explore the importance of boosting innovation in the wood technology sector by using a multidisciplinary approach In this compelling feature about wood technology, we learn that wood is one of the best materials to develop both multifunctional...
Polychlorinated biphenyls (PCBs): A continuing environmental health concern
This compelling article is written by Professor of Neurotoxicology, Pamela J. Lein, Ph.D. who is based at University of California's Davis/School of Veterinary Medicine. The thrust of the article is that polychlorinated biphenyls (PCBs) are a continuing environmental health concern in today's world Not shying away from detail, the piece...
From research to consumer: Demands for healthy, nutritious and innovative food
In this in-depth feature, we find out how the multidisciplinary HealthyMinorCereals project responds to consumers' increasing demands for healthy, nutritious and innovative food A spokesperson from the HealthyMinorCereals reveals their thoughts on the demands of today's consumers for food that is healthy, nutritious, innovative and produced sustainably. This in-depth article...
Why does Heterocyclic Chemistry matter?
Professor Colin J Suckling of University of Strathclyde explores the reasons why Heterocyclic Chemistry matters in the world today
Institute of Pathology – the treatment of paediatric cancer
Experts from the University of Lausanne explore progress being made in the treatment of paediatric cancer in this fascinating ebook
Genomic Research Laboratory – Staphylococcus aureus infections
Dr Patrice Francois describes the evolution of Staphylococcus aureus and highlights the challenge of managing it in hospitals and healthcare facilities
New functions of HTT in gene expression
Naoko Tanese from New York University explores how monitoring gene expression can be used to treat neurodegenerative diseases such as Huntington's
EUFAR promotes airborne research
EUFAR supports and develops airborne research projects to boost earth system understanding and weather prediction innovation in Europe
Using rainfall to understand climate change
The School of Civil Engineering and Geosciences at Newcastle University explains how data from rainfall can be used to help adapt to climate change
Asteroseismology: utilising the full extent of its power
The Max Planck Institute for Solar System Research highlights asteroseismology and what we can learn from the stars and their oscillations
Reducing energy consumption through optimised robot systems
Bengt Lennartson at Chalmers University of Technology explains how you can save up to 30% of energy and 50% peak power by optimised robot systems
FinnFusion: advancing fusion research in Finland
The FinnFusion Consortium outlines how fusion energy could be a potential energy source in Finland and be the key to the country becoming carbon neutral
Innovine project: adapting vineyards to climate change
How can The Innovine Project help vineyard growers throughout the EU develop better quality vines in a world where climate change is a key challenge?
Aircraft loads: What are they and why are they important?
Many aerospace engineering degree courses do not focus on aircraft loads, despite its importance. The ALPES project is changing this via new technologies
Embrace the possible: Tackling climate change with technology
Earth's climate is changing, but this has been happening since its creation; to deal with anthropogenic climate change we need to embrace technology
Latest Research Reports
Finding safer substitutes for endocrine disruptors is a tricky job
Voice biomarkers that identify driving skills
Covid screening: Let private accredited laboratories show their worth
Contaminants and infections: a link to explore
Latest Research eBooks
The Search for Dark Matter
Improving cattle production by counting chromosomes
Organophosphate Chemical Threat Agents: Contemporary solutions to a historic threat


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Become a Better Driver Learning in Edinburgh
By Angus	September 9, 2016 November 12th, 2016 Driving Lessons
Having been a driving instructor for the last six years, I have been to a range of driving test areas in the areas surrounding where I live. These would consist of Edinburgh both the Musselburgh and Currie test centres, Peebles and Lanark. Of course, every test centre will have its little challenges and tricky bits of road in the surrounding areas, but I feel that the difference between learning to drive in Edinburgh compared to these quieter towns is extremely noticeable. Living in Carlops which is just fifteen minutes away from the edge of Edinburgh a lot of the people that I get to go out with are from West Linton. We have a few have the choice of two test areas from West Linton these would be Peebles or Edinburgh at the Currie test centre. I try to persuade as many of them as possible to pick Edinburgh even though Peebles has noticeably higher pass rate for the driving test. I feel that the experience and knowledge that you will acquire learning to drive in Edinburgh is worth every extra bit of time learning.
When I was seventeen, I was really interested in learning to drive and couldn't wait to begin. I learnt to drive in Edinburgh, and at the time the driving test centre was at Sighthill in Edinburgh. This pretty much guaranteed that I was going to go through the roundabouts on Calder Road, the same ones that are still used today on the Currie test route of Edinburgh. I had to master these before there was any point of me sitting a test. I remember finding them challenging and trying to work out when to go and read what other people were going to do. Slowly it all started to make sense. After passing my test, I was out in my car constantly. I was exploring parts of Edinburgh with friends and driving to a range of events and venues where a lot of the time I would be driving on roads that I had never driven on before. I was taking on roundabouts that while taking driving lessons in Edinburgh I had never been near. I don't ever remember feeling phased though! I had a plan and stuck to it, of course, sometimes I might end up going the wrong way or getting lost, but I don't remember panicking or feeling stressed out.
Someone I was teaching to drive earlier this year, who was doing very well with the driving. We at the stage of just practising things and getting a bit more consistency during driving lessons, before booking a driving test was telling me a story. They were telling me that one of their friends had passed their driving test in Peebles with no driving faults, this is full marks which is an incredible achievement! The next week this person gave them a lift up into Edinburgh from Peebles, everything was going well through Peebles as the departed to head for Edinburgh. As they got towards the outskirts of Edinburgh, they had a few roundabouts that they had to go straight on at. The person I was teaching to drive said they noticed that the individual from Peebles positioning was wandering a little bit, they said he didn't comment as I'm sure it wouldn't go down to well. As they got closer to Edinburgh they had to drive through Gowkley Moss Roundabout which is just outside Penicuik, this roundabout is a spiral roundabout which they don't have in Peebles. According to the person I was teaching to drive the person from Peebles froze as they were just about to enter the roundabout saying "I don't know what to do here". Luckily the person I was teaching to drive had been though many spiral roundabouts when learning to drive in Edinburgh and talked their friend through it. Now it isn't the person from Peebles' fault, as when you look at the road setup in the area they have learnt to drive in you can only turn left or right at a roundabout. They have obviously managed to take in and demonstrated to an examiner that they could drive well, but the level is nothing compared to learning to drive in Edinburgh
In the clip featured above is the exact thing. Someone lacking the experience of learning to drive in Edinburgh, or a city environment might do. If you watch the featured car, it starts in the middle lane, then changes to the left before returning to the middle lane. Then the most dangerous bit it turns right from the left lane crossing the path of a red car.
Edinburgh driving Lessons Home
Reverse Parking Explained in 45 Seconds Edinburgh Driving Lessons October 12, 2016
Does Edinburgh Need to Become a 20mph City September 9, 2016
Become a Better Driver Learning in Edinburgh September 9, 2016
Edinburgh Bus Lane Operation Times Changing September 30, 2015
Address: Linnburn Cottage, Carlops, Scottish Borders, EH26 9NH
Email: angusdriving@gmail.com
© 2020 Angus Driving. All Rights Reserved | Web Design By Used Future Digital


Download A Dog's Tale movie for iPod/iPhone/iPad in hd, Divx, DVD or watch online.
When a young boy makes a wish on a Christmas Star for a pet dog, he gets more than expected when he becomes a dog. He must now find the secret to become a boy once again.


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Music Friday: The Rolling Stones Release Kaleidoscopic Lyric Video of 1967's 'Ruby Tuesday'
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Welcome to Music Friday when we bring you great songs with jewelry, gemstones or precious metals in the title or lyrics. Today, we present The Rolling Stones' newly released, kaleidoscopic lyric video of their 1967 smash hit, "Ruby Tuesday." The video premiered on Tuesday, of course, to promote the group's 2018 European tour, which kicks off tonight in London.
Composed by Keith Richards and Mick Jagger, the hauntingly beautiful ballad is our pick for the most popular "ruby" song of all time — even though it's about a lost love and not about the coveted scarlet gemstone.
The famous reprise goes like this… "Goodbye Ruby Tuesday / Who could hang a name on you? / When you change with every new day / Still I'm gonna miss you."
The lyric video delivers a throwback vibe on a number of levels. The producers used the original mono recording and illustrated the lyrics with brightly colored floral and paisley graphics reminiscent of the 1960s hippie era. The choruses cut to kaleidoscopic patterns set against a bright ruby red backdrop, ensuring a big hit of color in contrast to the verses.
In his autobiography, Richards noted that "Ruby Tuesday" was inspired by an emotionally devastating breakup with his girlfriend, Linda Keith, who left him for a poet.
"That's the first time I felt the deep cut," he explained. "The thing about being a songwriter is… you can find consolation in writing about it, and pour it out… It becomes an experience, a feeling, or a conglomeration of experiences. Basically, Linda is 'Ruby Tuesday.'"
The Rolling Stones released the original 45 of "Ruby Tuesday" in January of 1967 and the song immediately ascended to #1 on the U.S. Billboard Hot 100 chart. Rolling Stone magazine ranked the song #310 on its list of the 500 Greatest Songs of All Time.
"Ruby Tuesday" had been intended as the B side of "Let's Spend The Night Together," another Stones hit, but radio deejays at the time were uncomfortable with the adult theme of the A side, and chose to play the flip. Today, the 45 is referred to as a double-A-sided record.
The Rolling Stones are credited with more than 250 million album sales. They are members of the Rock and Roll Hall of Fame and were ranked fourth on Rolling Stone magazine's list of the "100 Greatest Artists of All Time."
Septuagenarian rockers Jagger, Richards, Charlie Watts and Ronnie Wood will be performing "Ruby Tuesday" on their "No Filter" tour, which runs through July 8 and will take the band throughout Europe.
Please check out the new video of "Ruby Tuesday." The lyrics are below if you'd like to sing along…
Written by Keith Richards and Mick Jagger. Performed by The Rolling Stones.
She would never say where she came from
Yesterday don't matter if it's gone
While the sun is bright
Or in the darkest night
No one knows, she comes and goes
Goodbye Ruby Tuesday
Who could hang a name on you?
When you change with every new day
Still I'm gonna miss you
Don't question why she needs to be so free
She'll tell you it's the only way to be
She just can't be chained
To a life where nothings gained
And nothings lost, at such a cost
"There's no time to lose," I heard her say
Catch your dreams before they slip away
Dying all the time
Lose your dreams and you will lose your mind
Ain't life unkind?
Credits: Screen capture via YouTube.com.


Looking for info regarding the MAWB Retreat? Click here for details and to register.
Established Jan 8, 2018, the Mississauga & Area Women in Business (MAWB) is the fastest-growing, most dynamic networking group for women based out of Mississauga. The members of MAWB, also known as MAWBsters, are local women, from MIssissauga and the surrounding communities, who come together to support each other's businesses, offer advice and encouragement, and foster both business relationships and real friendships.
With organized activities, both in-person and virtual, the members get to know each other on a personal level first, rather than just as a potential client pool. Aggressive sales tactics are actually dissuaded, but Theme Days exist on the Facebook Group Page to promote your business. The Facebook Group boasts an incredibly active and engaged community, with an over 75% participation rate from group members.
Its current incarnation was established by Christine Hull at the beginning of 2018. The group has since experienced exponential growth and morphed into a dynamic group of active, engaged women from all walks of life, in all types of businesses. Whether you are part of an MLM as a "side hustle" to your day job or to supplement family income, a business professional, or an employee of a larger company looking to expand your network, there is a place for you in the MAWB!
And other, more spontaneous activities, such as one-on-one coffee dates between members, non-coffee dates (i.e., cocktails!), golf outings, or even Networking Playdates for moms with young kids.
And a monthly Instagram challenge to encourage consistent Social Media activity and presence.
I would love to give credit to the MAWBster who wrote this piece, Xanthe LeBlanc. Visit her FB page, X-Rated Food Blog.
If you are looking to expand the awareness of your business in the marketplace, and well as develop a trusted pool of business advisors and mentors, the Mississauga & Area Women in Business could be the group for you. Please take a few minutes to explore our site to see what we have to offer. You won't be disappointed!


The oil/soy sauce filling machine generally adopts flow meter type filling, and the flow meter type filling is the computer to automatically track the temperature and density changes of the oil at any time to adjust the amount of oil delivery. The quality of oil delivery reduce errors due to temperature and density changes,high measurement accuracy.
The bottle is conveyed through the air duct to oil/soy sauce filling machine. Bottle holder is equipped with a bottle clamp on the rotary plate, and the bottle clamp clamps the bottle mouth and flips 180° along a guide rail so that the bottle mouth enters into the bottle rinser. In a specific area of the rinser, a special nozzle sprays flush water to rinse the inner wall of the bottle. After the bottle has been rinsed, drained and then clamped in the bottle holder along the guide again flip 180 °, so that the bottle up. The washed bottles are exported from the bottle rinser through the bottle-star wheel and delivered to the oil filling machine. The bottle that enters the filling equipment is held by the bottleneck holding plate, and is lowered and raised by the elevator mechanism under the action of the cam. The filling adopts the gravity filling method, the bottle mouth rises and the top filling valve is filled to complete the filling process. At the end of filling, the bottle drops off the filling valve. The bottle enters the capping machine through the card necking transition dial. The rotary knife on the capping machine grips the bottleneck and keeps the bottle upright to prevent rotation. The capping head keeps rotating and rotates on the capping machine, and the capping, capping, capping, and capping actions are performed under the action of the cam to complete the entire capping process. The finished bottle is conveyed from the capping machine to the delivery conveyor chain through the delivery trolley, and a three-in-one bottle dispenser is sent out from the conveyor chain. The whole equipment is closed, the height of the sealing window is higher than the highest point of the equipment, and proper channels are left in and out of the bottle, and a ventilation slot is left at the bottom of the sealing window.
All the rotating discs are welded with stainless steel SUS304.
The rubber grip of the bottle clamp grips the mouth of the bottle and is solid and reliable.
Using imported special high-efficiency spray nozzles, the flushing water is sprayed at a set angle and can be flushed to any part of the inner wall of the bottle, flushing thoroughly and saving the flushing water.
The bottle clamps and sliding sleeves of the lifting mechanism are all made of German corrosion-resistant maintenance-free bearings.
The power of the bottle rinsing machine is transmitted by the transmission system inside the rack through gears.
The oil filling machine's rotating plate is made of stainless steel SUS304.
The filling method is gravity filling.
The structure of the filling valve is reasonable and the filling volume is accurate.
During the filling process of the oil and soy sauce, the bottle valve is not moved, the bottleneck of the bottleneck catches the bottle mouth, and the lifting and lowering mechanism achieves a drop and rise under the action of the cam.
Liquid tank liquid level control method is float ball control.
The power of the soy filling machine is transmitted through the gears in the rack through the gears.
In the process of flushing, filling and capping connecting wheels and caps, the ring-shaped bottle-neck conveying method is adopted.
The falling cover guide rail is provided with a mechanism for preventing the reverse cover from passing through and a reverse cover removal mechanism. A set of photoelectric switches is also installed. When the cover guide rail has no cover, the operation of the machine is automatically stopped, which effectively avoids the occurrence of an uncovered bottle.
The bottle cap detection switch of the capping machine is provided, and the cap cylinder linked with the cap cover rail and the dial plate is used to control the discharge of the bottle cap to ensure that the cap feeding is stopped when there is no bottle, and the loss of the user's cap is reduced.
Efficient centrifugal cover, cover wear small.
A bottle cap detection mechanism is provided for controlling the opening and stopping of the cap lifter.