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ABSTRACT: Obstructed defecation syndrome is a multifactorial disorder of the defecation process. Stapled transanal rectal resection has been used to restore function in patients suffering from obstructed defecation syndrome.
The aim of this study was to use preoperative and postoperative dynamic pelvic floor MRI combined with clinical parameters to evaluate the outcome of stapled transanal rectal resection.
A prospective cohort study was conducted in a tertiary care center.
A group of 140 women with obstructed defecation syndrome were evaluated.
All 140 patients were initially treated conservatively with laxatives, increased fluid intake, pelvic floor exercises, and biofeedback. Stapled transanal rectal resection was performed in 30 patients with rectocele who did not show improvement in symptoms after at least 6 months of conservative treatment.
Preoperative diagnostic workup consisted of dynamic pelvic floor MRI, clinical examination, coloscopy, and clinical scores (Cleveland Clinic constipation score, German Working group on Coloproctology continence score, and SF-36 quality-of-life questionnaire). Postoperatively, patients were reevaluated at 3 months by means of dynamic pelvic floor MRI, clinical examination, and clinical scores; clinical scores were repeated at 6 months after the operation.
Postoperative dynamic pelvic floor MRI performed after a median of 3.4 months showed a decrease in rectocele size from 3.3 (interquartile range, 2.8-3.8) cm to 1.5 (1.2-2) cm (P < .001). The number of patients with intussusception decreased from 21 (70%) before the operation to none after the operation (P < .001). The size of cystoceles did not change. The number of patients with incomplete evacuation was significantly reduced (P < .001). With a mean follow-up of 18 ± 4 months, patients showed a significant improvement in the quality-of-life score (P < .001) but not in the continence scores.
Stapled transanal rectal resection is an effective treatment option for patients with obstructed defecation syndrome associated with rectocele and intussusception.
Diseases of the Colon & Rectum 04/2011; 54(4):412-7. · 3.13 Impact Factor
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ABSTRACT: Long-term administration of PUFA is known to modulate immune functions and apoptotic pathways depending on the respective amount of n-6 and n-3 fatty acids (FA). Data on short-term effects on apoptotic pathways are rare. Apoptosis of splenic lymphocytes is the hallmark of detrimental sepsis. Therefore, we aimed to compare the immediate effects of parenterally administered n-6-enriched soyabean oil (SO)- and n-3-enriched fish oil (FO)-based lipid emulsions after laparotomy (LAP; sham procedure) and after induction of acute, severe sepsis by caecal ligation and incision. After 390 min of observation time, plasma was analysed for IL-1β, IL-6 and NEFA. Apoptosis in splenic lymphocytes was quantified by Annexin-V expression. After LAP, infusion of both FO and SO did not change cytokine concentrations. Sepsis increased both cytokines. FO but not SO further augmented the rise. After LAP, SO increased NEFA, and both lipid emulsions reduced free arachidonic acid (AA). Sepsis resulted in a dramatic decrease in NEFA and AA. The drop in NEFA and AA was prevented by both SO and FO. In addition, FO resulted in an increased concentration of n-3 FA under both conditions. Infusion of both lipid emulsions induced apoptosis in splenic lymphocytes after LAP. Sepsis-induced apoptosis was not further enhanced by FO or SO. The present study shows that short-term administration of FO as opposed to SO caused pro-inflammatory effects during sepsis. Moreover, short-term administration of both SO and FO suffices to induce apoptosis in splenic lymphocytes. Finally, SO and FO do not further enhance sepsis-induced splenic apoptosis.
The British journal of nutrition 01/2011; 106(1):27-32. · 3.45 Impact Factor
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Matthias Hecker,
Zbigniew Zaslona,
Grazyna Kwapiszewska,
Gero Niess,
Anna Zakrzewicz,
Eduard Hergenreider,
Jochen Wilhelm,
Leigh M Marsh,
Daniel Sedding,
Walter Klepetko,
Jürgen Lohmeyer,
Stefanie Dimmeler,
Werner Seeger,
Norbert Weissmann,
Ralph T Schermuly,
Nikolaus Kneidinger,
Oliver Eickelberg,
Rory E Morty
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ABSTRACT: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed.
The objective of this study was to assess the possible contribution of the IL-13 system to IPAH.
Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC.
Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G(0)/G(1) arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects.
The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH.
American Journal of Respiratory and Critical Care Medicine 09/2010; 182(6):805-18. · 11.08 Impact Factor
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ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterised by accumulation of activated (myo)fibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of (myo)fibroblasts may be attributed, in part, to the process of transforming growth factor beta1 (TGFbeta1)-induced epithelial-mesenchymal transition (EMT), the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II (ATII) cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in IPF.
Using quantitative reverse transcription-PCR (RT-PCR), immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFbeta1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human IPF in vivo.
TGFbeta1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA (siRNA)-mediated SNAI depletion attenuated TGFbeta1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human IPF and localised to hyperplastic ATII cells in vivo.
The results demonstrate that TGFbeta1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human IPF in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.
Thorax 10/2009; 64(12):1053-61. · 6.84 Impact Factor
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ABSTRACT: Acute lung injury (ALI) and sepsis are the major causes of mortality in intensive care units. Lymphocytes apoptosis is a hallmark feature of late detrimental sepsis. Parenteral nutrition in critically ill patients is based on lipid emulsions, but the impact of ALI and lipid emulsions on lymphocytes has not been defined. The effects of intravenously infused conventional soybean oil (SO)-based and new olive oil (OO)-based emulsions on splenic and blood lymphocytes were investigated in a murine model of endotoxin-induced ALI. After LPS challenge and infusion of lipid emulsions, apoptosis of lymphocytes and lung injury were assessed by flow cytometry, Western blot, and histology. Induction of ALI led to a time-dependent decline in splenic and circulating lymphocyte numbers and an increase in apoptosis, with engagement of the extrinsic apoptotic pathway. Both SO- and OO-based emulsions promoted the apoptosis of splenic lymphocytes before induction of ALI. The OO-based emulsions exhibited lower proapoptotic activity than did SO-based emulsions, an observation paralleled by the induction of survival factors. Induction of ALI increased the mortality of mice receiving SO-based emulsions compared with OO-based emulsions and normal saline. Splenic lymphocyte apoptosis is apparent in murine ALI, which may be linked to detrimental outcome. Infusion of lipid emulsions per se provoked splenic lymphocyte apoptosis. Infusion of SO-based emulsions further augmented the apoptosis of splenic and circulating lymphocytes in ALI and led to increased mortality in mice. These findings may be of relevance for patients experiencing ALI that require parenteral nutrition.
Shock (Augusta, Ga.) 06/2009; 33(2):179-88. · 2.87 Impact Factor
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ABSTRACT: Interleukin-21 (IL-21), a member of the type I cytokine family, regulates central functions of immunity. Within this family, signaling is mediated via a receptor complex consisting of a high-affinity receptor chain and the common gamma-chain (IL-2Rgamma, CD132). We analyze the mRNA expression of IL-21, IL-21 receptor-alpha (IL-21Ralpha) and family members IL-15, IL-2Rgamma, IL-21Ralpha, IL-15Ralpha, IL-2/15Rbeta, as well as IL-2Ralpha (CD25) in leukocytes isolated by vascular perfusion of rat renal allografts. Mononuclear leukocytes expressed increased amounts of IL-21Ralpha mRNA and protein during acute rejection. Most IL-21Ralpha-positive cells were monocytes. Furthermore, IL-21 and IL-2Ralpha mRNA expression was strongly increased. No changes in IL-2Rgamma, IL-2/15Rbeta, IL-15, and IL-15Ralpha mRNA expression levels were seen. In conclusion, we demonstrate that IL-21Ralpha expression is induced in intravascular monocytes in vivo in response to allogeneic transplantation. The function of the IL-21/IL-21R system in monocytes and during acute allograft rejection remains to be established.
Immunobiology 02/2009; 214(1):41-9. · 3.20 Impact Factor
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Konstantin Mayer,
Almuth Kiessling,
Juliane Ott,
Martina Barbara Schaefer, Matthias Hecker,
Ingrid Henneke,
Richard Schulz,
Andreas Günther,
Jingdong Wang,
Lijun Wu,
Joachim Roth,
Werner Seeger,
Jing X Kang
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ABSTRACT: Acute lung injury (ALI) remains an important cause of mortality in intensive care units. Inflammation is controlled by cytokines and eicosanoids derived from the n-6 fatty acid (FA) arachidonic acid (AA). The n-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and mediators derived from EPA and DHA possess reduced inflammatory potency.
To determine whether the ability of fat-1 mice to endogenously convert n-6 to n-3 FA, and thus generate an increased ratio of n-3 to n-6 FA, impacts experimental ALI.
We investigated ALI induced by intratracheal instillation of endotoxin in fat-1 and wild-type (WT) mice, assessing leukocyte numbers, protein concentration, and prostaglandin and cytokine levels in bronchoalveolar lavage fluid, as well as free FA in plasma, and lung ventilator compliance. Body temperature and motor activity of mice--markers of sickness behavior--were also recorded.
In ALI, fat-1 mice exhibited significantly reduced leukocyte invasion, protein leakage, and macrophage inflammatory protein-2 and thromboxane B(2) levels in lavage fluid compared with WT mice. Free AA levels were increased in the plasma of WT mice in response to endotoxin, whereas EPA and DHA were increased in the fat-1 group. Ventilator compliance was significantly improved in fat-1 mice. Body temperature and motor activity were decreased in ALI. fat-1 Mice recovered body temperature and motor activity faster.
fat-1 Mice exhibited reduced features of ALI and sickness behavior. Increasing the availability of n-3 FA may thus be beneficial in critically ill patients with ALI.
American Journal of Respiratory and Critical Care Medicine 02/2009; 179(6):474-83. · 11.08 Impact Factor
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ABSTRACT: SUMMARY: Acute respiratory distress syndrome (ARDS) is a common clinical disorder caused by a variety of direct and indirect injuries to the lung, characterized by alveolar epithelial and endothelial injury resulting in damage to the pulmonary alveolar-capillary barrier. The cardinal clinical feature of ARDS, refractory arterial hypoxemia, is the result of protein-rich alveolar edema with impaired surfactant function, due to vascular leakage and vascular dysfunction with consequently impaired matching of ventilation to perfusion. Since its first description in 1967, considerable knowledge concerning the pathogenesis of ARDS has been obtained, however, a plethora of questions remain. Better understanding of the pathophysiology of ARDS has lead to the development of novel therapies, pharmacological strategies, and advances in mechanical ventilation. However, lung-protective ventilation is the only confirmed option in ARDS management improving survival, and few other therapies have translated into improved oxygenation or reduced ventilation time. But despite improvement in our understanding of the therapy and supportive care for patients with ARDS, mortality remains high. It is the purpose of this article to provide an overview of the definition, clinical features, and pathogenesis of ARDS, and to present and discuss therapeutic options currently available in order to effectively treat this severe disorder.
Transfusion Medicine and Hemotherapy 01/2008; 35(2):80-88. · 1.16 Impact Factor
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Anna Zakrzewicz, Matthias Hecker,
Leigh M Marsh,
Grazyna Kwapiszewska,
Bozena Nejman,
Lu Long,
Werner Seeger,
Ralph T Schermuly,
Nicholas W Morrell,
Rory E Morty,
Oliver Eickelberg
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ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by selective elevation of pulmonary arterial pressure. The pathological hallmark of PAH is the narrowing of pulmonary arterioles secondary to endothelial cell dysfunction and smooth muscle cell proliferation. Heterozygous mutations in BMPR2, encoding the type II bone morphogenetic protein receptor (BMPRII), were identified in PAH, suggesting that alterations to BMPRII function are involved in disease onset and/or progression.
We identified the receptor for activated C-kinase (RACK1) as a novel interaction partner of BMPRII by yeast 2-hybrid analyses using the kinase domain of BMPRII as a bait. Glutathione-S-transferase pull-down and coimmunoprecipitation confirmed the interaction of RACK1 with BMPRII in vitro and in vivo. RACK1-BMPRII interaction was reduced when kinase domain mutations occurring in patients with PAH were introduced to BMPRII. Immunohistochemistry of lung sections from PAH and control patients and immunofluorescence analysis of primary pulmonary arterial smooth muscle cells demonstrated colocalization of BMPRII and RACK1 in vivo. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis showed significant downregulation of RACK1 expression in the rat model of monocrotaline-induced PAH but not in pulmonary arterial smooth muscle cells from PAH patients. Abrogation of RACK1 expression in pulmonary arterial smooth muscle cells led to decreased Smad1 phosphorylation and increased proliferation, whereas overexpression of RACK1 led to increased Smad1 phosphorylation and decreased proliferation.
RACK1, a novel interaction partner of BMPRII, constitutes a new negative regulator of pulmonary arterial smooth muscle cell proliferation, suggesting a potential role for RACK1 in the pathogenesis of PAH.
Circulation 07/2007; 115(23):2957-68. · 14.74 Impact Factor
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Rory E Morty,
Bozena Nejman,
Grazyna Kwapiszewska, Matthias Hecker,
Anka Zakrzewicz,
Fotini M Kouri,
Dorothea M Peters,
Rio Dumitrascu,
Werner Seeger,
Petra Knaus,
Ralph T Schermuly,
Oliver Eickelberg
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ABSTRACT: Mutations in the bmpr2 gene, encoding the type II bone morphogenetic protein (BMP) receptor, have been identified in patients with pulmonary arterial hypertension (PAH), implicating BMP signaling in PAH. The aim of this study was to assess BMP signaling and its physiological effects in a monocrotaline (MCT) model of PAH.
Expression of BMP receptors Ib and II, and Smads 4, 5, 6, and 8, was downregulated in lungs but not kidneys of MCT-treated rats. Smad1 phosphorylation and expression of BMP/Smad target genes id1 and id3 was also reduced, although ERK1/2 and p38(MAPK) phosphorylation remained unaffected. BMP receptor and Smad expression, Smad1 phosphorylation, and induction of the BMP/Smad-responsive element of the id1 promoter were reduced in pulmonary artery smooth muscle cells (PASMCs) from MCT-treated rats. As a consequence of impaired BMP/Smad signaling, PASMCs from MCT-treated rats were resistant to apoptosis induced by BMP-4 and BMP-7, and were also resistant to BMP-4 antagonism of proliferation induced by platelet-derived growth factor.
BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH.
Arteriosclerosis Thrombosis and Vascular Biology 06/2007; 27(5):1072-8. · 6.37 Impact Factor
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ABSTRACT: Vascular smooth muscle cells (VSMCs) constitute the major cellular component of the vessel tunica media. VSMC proliferation is a key feature in developing vessels and pathological states such as atherosclerosis and restenosis. Transforming growth factor (TGF)-beta is a key regulator of VSMCs, but its effect on VSMC proliferation and apoptosis are controversial. Here, we characterized TGF-beta effects on basal-, serum-, and platelet-derived growth factor-BB-induced primary mouse VSMC proliferation. TGF-beta led to potent growth inhibition of VSMCs isolated from normal mouse aortae without inducing apoptosis. Growth inhibition by TGF-beta was due to G0/G1 arrest. Next, we explored distinct signaling pathways activated by TGF-beta and the effects of pharmacological inhibition of these. TGF-beta led to activation of Smad2/3, p38, p42/44, and c-Jun NH2-terminal kinase (JNK) pathways, assessed by phosphorylation, immunofluorescence, and reporter gene analysis. TGF-beta-dependent growth inhibition was specifically attenuated by pharmacological blockade of the TGF-beta type I receptor (TbetaRI) kinase or p38 mitogen-activated protein kinase pathways, whereas blockade of p42/44 or JNK kinases did not influence the effect of TGF-beta. TbetaRI kinase inhibition blocked all downstream pathways including Smad and p38 phosphorylation. In contrast, p38 inhibition did not alter Smad function, as assessed by translocation or reporter gene expression, but selectively inhibited p38 activity. These results demonstrate that TGF-beta acts as a potent antiproliferative mediator in VSMCs, irrespective of the proliferative stimulus, without inducing apoptotic effects. The anti-proliferative effect of TGF-beta is due to G0/G1 arrest and mediated primarily by the p38 pathway, suggesting that p38 kinase is central to TGF-beta-mediated growth inhibition in primary mouse VSMCs.
Journal of Pharmacology and Experimental Therapeutics 01/2006; 315(3):1005-12. · 3.83 Impact Factor
