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Local Release (local + release)
Selected AbstractsSerotonin content of normal and inflamed appendix: a possible role of serotonin in acute appendicitis,APMIS, Issue 11 2008MOHAMMAD VASEI The appendix is lined by a mucosa which has many neuroendocrine cells containing serotonin. Local release of serotonin can act as a mediator of inflammation. In this study we explored the serotonin content of the neuroendocrine cells of the appendixes removed for clinical diagnosis of appendicitis. Appendix specimens were divided into three groups: Acute appendicitis (AA), non-appendicitis (NA), and follicular hyperplasia (FH). Normal appendix specimens from patients undergoing elective abdominal surgery were used as the control group (NL). All sections were exposed to proteinase K, incubated with anti-serotonin, chromogranin A, and synaptophysin antibodies, and treated with the LSAB kit. Polygonal cells were seen within the crypt epithelium (enterochromaffin cell, EC) and within the lamina propria (subepithelial neuroendocrine cell, SNC). In AA, only 16 cases (64%) showed serotonin staining in non-destructed glands. There was a significant reduction in the number of ECs in AA compared to the FH (96%), NA (100%) and NL (100%) groups (P<0.001). Chromogranin and synaptophysin immunostaining also showed a significant reduction in the number of ECs in AA compared with the other three groups (P<0.001). SNC serotonin reactivity was lower in the AA group compared with the other groups (p<0.001). The inflamed appendix is markedly depleted of serotonin in the epithelium and lamina propria. Local serotonin release from ECs and SNCs in the appendix may act as an inflammatory mediator in appendicitis and is likely to be the source of raised blood serotonin in AA. [source] Local release of eosinophil peroxidase following segmental allergen provocation in asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 3 2003V. J. Erpenbeck Summary Background Eosinophil peroxidase (EPO) is an eosinophilic basic protein, which leads to increased permeability and damage of bronchial epithelial cells in asthma. Objective As little is known about its local expression and release in humans the intracellular expression in lung and peripheral eosinophils and the concentrations of EPO in bronchoalveolar lavage (BAL) fluid and serum was investigated in patients with asthma. Methods Twelve mild atopic asthmatic and nine control subjects underwent segmental sham and allergen challenge. EPO concentrations in BAL fluid and serum were determined by immunoassay and flow cytometry was used to determine the intracellular expression of EPO in BAL-derived and peripheral eosinophils. Results In asthmatic patients a large increase in BAL eosinophils , total cells: median 9.5 × 106 (range: 0.5 to 455.0 × 106); relative: 38% (1 to 91%) , was detectable 24 h following allergen challenge, but peripheral blood eosinophil counts did not change. Concentrations of EPO in BAL fluid increased from 1 µg/L (1.0 to 6.8 µg/L) to 42 µg/L (5.6 to 379.6 µg/L; P < 0.01) after allergen but not after saline challenge (1.5 µg/L; 1.0 to 21.9 µg/L), whereas in control subjects all measurements were below the detection limit. Serum concentrations of EPO increased slightly from 18.3 µg/L (3.0 to 56.8 µg/L) to 27 µg/L (3.8 to 133.9 µg/L; P < 0.05) 24 h after allergen challenge in asthmatic patients. Furthermore, the intracellular expression of EPO (measured as mean fluorescence intensity) was decreased in BAL eosinophils compared with blood eosinophils (mean fluorescence intensity 29 (7 to 71) vs. 48 (20 to 85); P < 0.01) after allergen challenge. Conclusion The finding of increased EPO concentrations in the BAL fluid and decreased intracellular EPO expression in pulmonary eosinophils of asthmatic patients reflects the allergen-triggered release of EPO into the bronchial space. [source] The Neurogenic Vasodilator Response to Endothelin-1: A Study in Human Skin In VivoEXPERIMENTAL PHYSIOLOGY, Issue 6 2000Ruwani Katugampola We have investigated the mediators and mechanisms underlying the vasodilator effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its isomers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to quantify the release of mediators within the dermal response and scanning laser Doppler imaging to measure changes in blood flux. The effects of local anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET receptor blockade on the ET-induced vascular response were also investigated. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by a long-lasting flare which was accompanied by a short-lived burning pruritus. The concentration of nitric oxide (NO) in dialysate collected within the pallor response to 5 ,M ET-1 (1.43 ± 0.64 ,M, n = 5) was not significantly different from baseline levels collected prior to injection (0.86 ± 0.38 ,M) whilst that in the flare increased to reach a peak value of 2.28 ± 0.61 ,M at between 4 and 10 min after intradermal injection (P < 0.004). Pretreatment with local anaesthetic slowed the development of the flare and significantly reduced its size by up to 52% at 20 min after injection (P < 0.05) but had no significant effect on the central pallor. L-NAME, delivered by dialysis also caused a significant reduction in the ET-1-induced flare (P < 0.005). Bosentan, the non-selective ETA/ETB antagonist, when given by dialysis at the site of injection, reduced the area of both the ET-1-induced pallor and surrounding flare by 41 and 26%, respectively. No significant increase in tissue histamine was measured within either the pallor or flare response to ET-1, -2 or -3. Together these data confirm that the vasodilator response to endothelin-1 in human skin is neurogenic in origin and that it is in part mediated by the local release of nitric oxide. There appears to be little evidence for the involvement of mast cell-derived histamine in the initiation or modulation of ET-induced vasodilatation, in vivo. [source] Drug-eluting bead therapy in primary and metastatic disease of the liverHPB, Issue 7 2009Stewart Carter Abstract Background:, Drug-eluting bead transarterial chemoembolization (DEB-TACE) is a novel therapy for the treatment of hypervascuarized tumours. Through the intra-arterial delivery of microspheres, DEB-TACE allows for embolization as well as local release of chemotherapy in the treatment of hepatic malignancy, providing an alternative therapeutic option in unresectable tumours. Its role as an adjunct to surgical resection or radiofrequency ablation (RFA) is less clear. The purpose of this review is to summarize recent studies investigating DEB-TACE in order to better define safety, efficacy and outcomes associated with its use. Methods:, A systematic review of all published articles and trials identified nine clinical trials and 23 abstracts. These were reviewed for tumour histology, stage of treatment, delivery technique, outcome at follow-up, complications and mortality rates. Results:, Publications involved treatment of hepatocellular carcinoma (HCC), metastatic colorectal carcinoma (MCRC), metastatic neuroendocrine (MNE) disease and cholangiocarcinoma (CCA). Using Response Evaluation Criteria in Solid Tumours (RECIST) or European Association for the Study of the Liver (EASL) criteria, studies treating HCC reported complete response (CR) rates of 5% (5/101) at 1 month, 9% (8/91) at 4 months, 14% (19/138) at 6 months and 25% (2/8) at 10 months. Partial response (PR) was reported as 58% (76/131) at 1 month, 50% (67/119) at 4 months, 57% (62/108) at 6,7 months and 63% (5/8) at 10 months. Studies involving MCRC, CCA and MNE disease were less valuable in terms of response rate because there is a lack of comparative data. The most common procedure-associated complications included fever (46,72%), nausea and vomiting (42,47%), abdominal pain (44,80%) and liver abscess (2,3%). Rather than reporting individual symptoms, two studies reported rates of post-embolic syndrome (PES), consisting of fever, abdominal pain, and nausea and vomiting, at 82% (75/91). Six of eight studies reported length of hospital stay, which averaged 2.3 days per procedure. Mortality was reported as occurring in 10 of 456 (2%) procedures, or 10 of 214 (5%) patients. Conclusions:, Drug-eluting bead TACE is becoming more widely utilized in primary and liver-dominant metastatic disease of the liver. Outcomes of success must be expanded beyond response rates because these are not a reliable surrogate for progression-free survival or overall survival. Ongoing clinical trials will further clarify the optimal timing and strategy of this technology. [source] Local control of the immune response in the liverIMMUNOLOGICAL REVIEWS, Issue 1 2000Percy A. Knolle Summary: The physiological function of the liver , such as removal of pathogens and antigens from the blood, protein synthesis and metabolism , requires an immune response that is adapted to these tasks and is locally regulated. Pathogenic microorganisms must be efficiently eliminated while the large number of antigens derived from the gastrointestinal tract must be tolerized. From experimental observations it is evident that the liver favours the induction of tolerance rather than the induction of immunity. The liver probably not only is involved in transplantation tolerance but contributes as well to tolerance to orally ingested antigens (entering the liver with portal-venous blood) and to containment of systemic immune responses (antigen from the systemic circulation entering the liver with arterial blood). This review summarizes the experimental data that shed light on the molecular mechanisms and the cell populations of the liver involved in local immune regulation in the liver. Although hepatocytes constitute the major cell population of the liver, direct interaction of hepatocytes with leukocytes in the blood is unlikely. Sinusoidal endothelial cells, which line the hepatic sinusoids and separate hepatocytes from leukocytes in the sinusoidal lumen, and Kupffer cells, the resident macrophage population of the liver, can directly interact with passenger leukocytes. In the liver, clearance of antigen from the blood occurs mainly by sinusoidal endothelial cells through very efficient receptor-mediated endocytosis. Liver sinusoidal endothelial cells constitutively express all molecules necessary for antigen presentation (CD54, CD80, CD86, MHC class I and class II and CD40) and can function as antigen-presenting cells for CD4+ and CD8+ T cells. Thus, these cells probably contribute to hepatic immune surveillance by activation of effector T cells. Antigen-specific T-cell activation is influenced by the local microenvironment. This microenvironment is characterized by the physiological presence of bacterial constituents such as endotoxin and by the local release of immunosuppressive mediators such as interleukin-10, prostaglandin E2 and transforming growth factor-b. Different hepatic cell populations may contribute in different ways to tolerance induction in the liver. In vitro experiments revealed that naive T cells are activated by resident sinusoidal endothelial cells but do not differentiate into effector T cells. These T cells show a cytokine profile and a functional phenotype that is compatible with the induction of tolerance. Besides sinusoidal endothelial cells, other cell populations of the liver, such as dendritic cells, Kupffer cells and perhaps also hepatocytes, may contribute to tolerance induction by deletion of T cells through induction of apoptosis. [source] Disorder-specific changes in innervation in oral lichen planus and lichenoid reactionsJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 8 2000Sirkku Niissalo Abstract: The peripheral nervous system was analysed in the oral mucosa of eight patients with oral lichen planus (OLP), five with a lichenoid reaction (LR) and three with mild chronic inflammation (MCI), by morphometric analysis of nerve fibres containing immunoreactive PGP 9.5, substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), or C-flanking peptide of neuropeptide Y (CPON). Overall nerve fibre density was higher in OLP (P=0.039) and LR (P=0.026) compared with healthy oral mucosa and was compatible with sprouting and collateral formation. In contrast to the innervation visualized with structural nerve fibre-marker PGP 9.5, the densities of neuropeptide-immunoreactive nerves were low in inflamed tissue. This is consistent with depletion via local release. Retraction and local loss of innervation were found in areas coinciding with the most severe inflammation and basal membrane (BM) damage. Interestingly, LR showed a twenty-eight-fold loss of post-ganglionic CPON-ir sympathetic nerve fibres (P=0.044). In LR, CPON-ir innervation was markedly lower than in OLP. Finally, the pattern of innervation in relation to inflammatory cell infiltrates and tissue structures differed between OLP and LR. In conclusion, the peripheral nervous system is implicated in the immunopathogenesis of lichen planus and lichenoid reactions, with a disorder-specific difference in this involvement. [source] Improvement of peripheral nerve regeneration in acellular nerve grafts with local release of nerve growth factorMICROSURGERY, Issue 4 2009Hailong Yu M.D. Previous studies have demonstrated the potential of growth factors in peripheral nerve regeneration. A method was developed for sustained delivery of nerve growth factor (NGF) for nerve repair with acellular nerve grafts to augment peripheral nerve regeneration. NGF-containing polymeric microspheres were fixed with fibrin glue around chemically extracted acellular nerve grafts for prolonged, site-specific delivery of NGF. A total of 52 Wister rats were randomly divided into four groups for treatment: autografting, NGF-treated acellular grafting, acellular grafting alone, and acellular grafting with fibrin glue. The model of a 10-mm sciatic nerve with a 10-mm gap was used to assess nerve regeneration. At the 2nd week after nerve repair, the length of axonal regeneration was longer with NGF-treated acellular grafting than acellular grafting alone and acellular grafting with fibrin glue, but shorter than autografting (P < 0.05). Sixteen weeks after nerve repair, nerve regeneration was assessed functionally and histomorphometrically. The percentage tension of the triceps surae muscles in the autograft group was 85.33 ± 5.59%, significantly higher than that of NGF-treated group, acellular graft group and fibrin-glue group, at 69.79 ± 5.31%, 64.46 ± 8.48%, and 63.35 ± 6.40%, respectively (P < 0.05). The ratio of conserved muscle-mass was greater in the NGF-treated group (53.73 ± 4.56%) than in the acellular graft (46.37 ± 5.68%) and fibrin glue groups (45.78 ± 7.14%) but lower than in the autograft group (62.54 ± 8.25%) (P < 0.05). Image analysis on histological observation revealed axonal diameter, axon number, and myelin thickness better with NGF-treated acellular grafting than with acellular grafting alone and acellular grafting with fibrin glue (P < 0.05). There were no significant differences between NGF-treated acellular grafting and autografting. This method of sustained site-specific delivery of NGF can enhance peripheral nerve regeneration across short nerve gaps repaired with acellular nerve grafts. © 2009 Wiley-Liss, Inc. Microsurgery, 2009. [source] Effect of long-term application of epinephrine on rat skin vasculature: Experimental studyMICROSURGERY, Issue 7 2002Ercan Karacao, lu M.D. As a potent vasoconstrictor, epinephrine is used ubiquitously in plastic surgery. It is typically delivered subcutaneously in very low concentrations over a brief time interval. We are aware of no reports describing the long-term release of epinephrine as an independent agent to the soft tissues for the purpose of causing prolonged local vasoconstriction. This study was designed to address two goals: first, to investigate the effect of long-term local release of epinephrine from a drug delivery system on rat abdominal skin vasculature; secondly, to evaluate the pharmacological properties of this drug delivery system (DDS). Thirty male Sprague-Dawley rats, weighing 300,400 g, were included in the study. Animals were subdivided into two groups of 15 each. Group A (control group) and Group B (experimental group) were treated with saline and epinephrine-loaded microspheres (msps), respectively. The manufacturing process and formulation studies of the DDS are described. In vivo assays revealed a 7-day sustained release of epinephrine. After 7 days, neither residual nor supraphysiologic release of epinephrine was shown with high-performance liquid chromatography (HPLC). Histological studies with hematoxylin-eosin and periodic acid Schiff revealed a statistically significant increase in number of vessels as well as their diameter and wall thickness (P <0.05). Epinephrine release via this msp/DDS predictably induces local vasoconstriction over a time sequence known to be optimally associated with hypoxia and promotion of vascular augmentation. This model can be valuable in sustaining hemostasis during long-lasting (more than a few hours) surgical procedures by its long-acting vasoconstructive effect. The system's ability to intentionally cause vascular augmentation also bodes great potential in flap and graft surgery. © 2002 Wiley-Liss, Inc. MICROSURGERY 22:288,294 2002 [source] Bone repair with a form of BMP-2 engineered for incorporation into fibrin cell ingrowth matrices,BIOTECHNOLOGY & BIOENGINEERING, Issue 3 2005Hugo G. Schmoekel Abstract Most growth factors naturally involved in development and regeneration demonstrate strong binding to the extracellular matrix and are retained there until being locally mobilized by cells. In spite of this feedback between cell activity and growth factor mobilization in the extracellular matrix, this approach has not been extensively explored in therapeutic situations. We present an engineered bone morphogenetic protein-2 (BMP-2) fusion protein that mimics such function in a surgically relevant matrix, fibrin, incorporated into the matrix until it is locally liberated by cell surface-associated proteases. A tripartite fusion protein, denoted TG-pl-BMP-2, was designed and produced recombinantly. An N-terminal transglutaminase substrate (TG) domain provides covalent attachment to fibrin during coagulation under the influence of the blood transglutaminase factor XIIIa. A central plasmin substrate (pl) domain provides a cleavage site for local release of the attached growth factor from the fibrin matrix under the influence of cell-activated plasmin. A C-terminal human BMP-2 domain provides osteogenic activity. TG-pl-BMP-2 in fibrin was evaluated in vivo in critical-size craniotomy defects in rats, where it induced 76% more defect healing with bone at 3 weeks with a dose of 1 ,g/defect than wildtype BMP-2 in fibrin. After a dosing study in rabbits, the engineered growth factor in fibrin was evaluated in a prospective clinical study for pancarpal fusion in dogs, where it induced statistically faster and more extensive bone bridging than equivalent treatment with cancellous bone autograft. The strong healing response shown by fibrin including a bound BMP-2 variant suggests that with the combination of bound growth factor and ingrowth matrix, it may be possible to improve upon the natural growth factor and even upon tissue autograft. © 2004 Wiley Periodicals, Inc. [source] Angiotensin-(1-7) is involved in the endothelium-dependent modulation of phenylephrine-induced contraction in the aorta of mRen-2 transgenic ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2002Virgínia S Lemos The contribution of the local vascular production of angiotensin-(1-7) [Ang-(1-7)] to the control of ,-adrenergic-induced contractions in the aorta of Sprague-Dawley (SD) and TGR(mRen-2)27 [mRen-2] rats was studied. In mRen-2 rats, contractile responses to phenylephrine were diminished as compared to control SD rats in endothelium containing but not in endothelium-denuded vessels. L -NAME increased contractile responses to phenylephrine in mRen-2 rats and, after nitric oxide synthase blockade, responses to phenylephrine became comparable in both strains. Inhibition of angiotensin-converting enzyme (ACE) by captopril potentiated contractile responses in mRen-2 rats and diminished contractile responses in SD rats, both effects being dependent on the presence of a functional endothelium. The effect of captopril in mRen-2 rats was abolished in vessels pre-incubated with Ang-(1-7). Blockade of Ang-(1-7) and bradykinin (BK) receptors by A-779 and HOE 140 respectively, increased phenylephrine-induced contraction in mRen-2, but not in SD rats. This effect was seen only in endothelium-containing vessels. Angiotensin II AT1 and AT2 receptor blockade by CV 11974 and PD 123319 did not affect the contractile responses to phenylephrine in aortas of transgenic animals but diminished the response in SD rats. This effect was only seen in the presence of a functional endothelium. It is concluded that the decreased contractile responses to phenylephrine in aortas of mRen-2 rats was dependent on an intact endothelium, the local release and action of Ang-(1-7) and bradykinin. British Journal of Pharmacology (2002) 135, 1743,1748; doi:10.1038/sj.bjp.0704630 [source] | |||||||||||||