Surgical outcomes in survivors of childhood cancer undergoing thyroidectomy: A single-institution experience.

BACKGROUND: Childhood cancer survivors (CCS) are at increased risk for thyroid disease, and many require definitive management with thyroid surgery. Despite this, there is limited evidence on surgical outcomes among CCS. We sought to evaluate postoperative outcomes at our institution among CCS undergoing thyroid surgery compared to patients without a history of primary childhood malignancy. PROCEDURE: Medical records were reviewed for 638 patients treated at the Children's Hospital of Philadelphia Pediatric Thyroid Center between 2009 and 2020. Rates of surgical complications, including recurrent laryngeal nerve (RLN) paralysis and hypoparathyroidism, among CCS were compared to patients with sporadic/familial thyroid cancer, Graves' disease, and other benign thyroid conditions. Operative time and intraoperative parathyroid hormone levels were also evaluated. RESULTS: There were no significant differences in long-term surgical complication rates, such as permanent RLN paralysis and hypoparathyroidism, between CCS and patients without a history of primary childhood malignancy (all p > .05). For all surgical outcomes, there were no significant differences in complication rates when CCS were compared to those undergoing surgery for sporadic/familial thyroid cancer or Graves' disease (all p > .05). CCS with benign final pathology had significantly higher rates of transient hypoparathyroidism compared to patients with benign thyroid conditions (p < .001). CONCLUSIONS: Our study suggests that CCS are not at higher risk of long-term complications from thyroid surgery when treated by high-volume surgeons within a multidisciplinary team.

Optical polymers with tunable refractive index for nanoimprint technologies.

In order to realize a versatile high throughput production of micro-optical elements, UV-curable polymer composites containing titanium dioxide nanoparticles were prepared and characterized. The composites are based on an industrial prototype epoxy polymer. Titanium dioxide nanoparticles smaller than 10 nm were synthesized by the nonaqueous sol method and in situ sterically stabilized by three different organic surfactants. The composites exhibit high transparency. Distinct alteration of optical transmission properties for visible light and near IR wavelength range could be avoided by adaption of the stabilizing organic surfactant. Most importantly, the refractive index (RI) of the composites that depends on the fraction of incorporated inorganic nanoparticles could be directly tuned. E.g. the RI at a wavelength of 635 nm of a composite containing 23 wt% titanium dioxide nanoparticles is increased to 1.626, with respect to a value of 1.542 for the pure polymer. Furthermore, it could be demonstrated that the prepared inorganic-organic nanocomposites are well suited for the direct fabrication of low-cost micro-optical elements by nanoimprint lithography. A low response of the optical composite properties to temperature treatment up to 220 °C with a shrinkage of only about 4% ensures its application for integrated micro-optical elements in industrial production.

Clinical case seminar in pediatric thyroid disease.

Pediatric thyroid diseases cover a large spectrum of congenital and acquired forms, ranging from congenital primary or central hypothyroidism, autoimmune thyroid disease, iodine deficiency, rare genetic defects of thyroid hormone action, metabolism and cell membrane transport to benign nodules and malignant tumors. The previous 15 papers of the textbook Paediatric Thyroidology gave a systematic overview of the current knowledge and guidelines on all these diseases. In this final paper, the authors collected a series of patient histories from their clinics illustrating frequently encountered clinical problems and providing key learning points and references to each case. Although not fully comprehensive, it aims at providing relevant clinical knowledge on thyroid diseases of the neonate, the child, and the adolescent.

Evaluation of resistless Ga⁺ beam lithography for UV NIL stamp fabrication.

This paper presents an alternative rapid prototyping approach for the fabrication of stamps for UV nanoimprint lithography. In this process, areas implanted with gallium serve as an etch mask for the dry etching of quartz. The implantation is performed using a focused ion beam system. To avoid charging of the quartz substrate the use of thin layers of chromium or carbon on the quartz substrate has been evaluated. The resulting quartz structures exhibit very smooth surfaces after dry etching, if the implantation dose is high enough to form a stable etch mask. Furthermore, anisotropic etching could be realized by optimization of a quartz etching process involving C4F8 and O2 after the use of resistless Ga(+) beam lithography. Finally, imprints into a UV curing resist are performed successfully with the manufactured stamps, proving that the presence of Ga rich areas on the stamp is not detrimental to the curing of the resist or the functionality of the anti-sticking layer.

Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock.

BACKGROUND: Early murine endotoxin-induced ileus at 6 h is exclusively mediated by non-hemopoietic TLR4/MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role of hemopoietic cells in LPS/TLR4-triggered ileus and inflammation over time, and identify mechanisms of ileus. METHODS: CSF-1(-/-) , TLR4 non-chimera and TLR4 chimera mice were single-shot intraperitoneal injected with ultrapure lipopolysaccharide (UP-LPS) and studied up to 4 days. Subgroups of TLR4(WT) mice were additionally intravenously injected with exogenous recombinant IL-6 (rmIL-6) or murine soluble IL-6 receptor blocking antibody (anti-sIL-6R mAB). KEY RESULTS: Hemopoietic TLR4 signaling independently mediated UP-LPS-induced ileus at 24 h, but chemotactic muscularis neutrophil extravasation was not causatively involved and mice lacking CSF-1-dependent macrophages died prematurely. Synergy of hemopoietic and non-hemopoietic cells determined ileus severity and mortality which correlated with synergistic cell lineage specific transcription of inflammatory mediators like IL-6 within the intestinal muscularis. Circulating IL-6 levels were LPS dose dependent, but exogenous rmIL-6 did not spark off a self-perpetuating inflammatory response triggering ileus. Sustained therapeutic inhibition of functional IL-6 signaling efficiently ameliorated late ileus while preemptive antibody-mediated IL-6R blockade was marginally effective in mitigating ileus. However, IL-6R blockade did not prevent endotoxin-associated mortality nor did it alter circulating IL-6 levels. CONCLUSIONS & INFERENCES: A time-delayed bone marrow-driven mechanism of murine endotoxin-induced ileus exists, and hemopoietic cells synergize with non-hemopoietic cells thereby prolonging ileus and fueling intestinal inflammation. Importantly, IL-6 signaling via IL-6R/gp130 drives late ileus, yet it did not regulate mortality in endotoxic shock.

Circulating and utero-placental adaptations to chronic placental ischemia in the rat.

While utero-placental insufficiency is associated with adverse outcomes for both mother and fetus, many of the maternal-fetal adaptations during pregnancy in models of fetal compromise remain unclear. The purpose of this study was to determine if chronically reduced uterine perfusion pressure (RUPP) during days 14-19 of gestation alters feto-placental growth differentially from the cervical to ovarian ends of the uterus and generates metabolic adaptations such as increased blood lactate (BLa) concentrations and lactate transporter expression in the placenta. Fetal growth restriction was evident, placental efficiency (fetal weight/placental weight) decreased (4.7 ± 0.35 vs. 5.9 ± 0.30; P < 0.05) and fetal growth pattern within the uterus was altered in the RUPP compared to the normal pregnant (NP) rats. Blood lactate concentrations were increased (3.3 ± 0.3 vs. 2.1 ± 0.4 mmol/l; P < 0.05) in NP compared to virgin rats, and in RUPP compared to NP (5.0 ± 0.6 vs. 3.3 ± 0.3 mmol/l; P < 0.05). Lactate concentration was increased (10.0 ± 0.6 vs. 7.1 ± 0.8 mmol/l; P < 0.05) in the media from hypoxic compared to normoxic BeWo cells. No changes in expression of placental MCT1, 2, or 4 were observed between RUPP and NP rats. RUPP resulted in decreased plasma leptin (2.0 ± 0.3 vs. 3.1 ± 0.4; P < 0.05) but no change in IGF-1 compared to NP. The present data indicate chronic placental ischemia results in numerous endocrine and metabolic changes during late pregnancy in the rat and that the RUPP model has differential effects on fetal growth depending on uterine position.

Novel model of peripheral tissue trauma-induced inflammation and gastrointestinal dysmotility.

BACKGROUND: Trauma is a leading cause of death and although the gut is recognized as the 'motor' of post-traumatic systemic inflammatory response syndrome and multiple organ failure, studies on the gastrointestinal (GI) tract are few. Our objectives were to create a precisely controllable tissue injury model in which GI motility, systemic inflammation and wound fluid can be analyzed. METHODS: A non-narcotic murine trauma model was developed by the subcutaneous dorsal trans-implantation of a devitalized donor syngeneic harvested tissue-bone matrix (TBX), which was precisely adjusted to % total body weight and studied after 21 h. Gastrointestinal transit histograms were plotted after the oral administration of non-digestible FITC-dextran and geometric centers calculated. Organ bath evaluated jejunal circular muscle contractility. Multiplex electrochemiluminescence measurements of serum and TBX wound fluid inflammatory mediators were performed. KEY RESULTS: Increasing TBX amounts progressively delayed transit, whereas TBX heat denaturation or decellularization prevented ileus and death. In the TBX(17.5%) model, jejunal muscle contractility was suppressed and a systemic inflammatory response developed as significant serum elevations in IL-6, keratinocyte cytokine and IL-10 compared to sham. In addition, inflammatory responses within the wound fluid showed elevated levels of preformed IL-1ß and TNF-α, whereas, 21 h after implantation IL-1ß, IL-6 and keratinocyte cytokine were significantly increased in the wound. CONCLUSIONS & INFERENCES: A novel donor tissue-bone matrix trauma model was developed that is precisely adjustable and recapitulates important clinical phenomena. The non-narcotic model demonstrated that increasing tissue injury progressively caused ileus, initiated a systemic inflammatory response and developed inflammatory changes within the wound.

Anti-inflammatory role of glycine in reducing rodent postoperative inflammatory ileus.

BACKGROUND: Inflammatory events within the intestinal muscularis, including macrophage activation and leukocyte recruitment, have been demonstrated to participate in causing postoperative ileus. Recently, glycine has gained attention due to its beneficial immunomodulatory effects in transplantation, shock and sepsis. METHODS: Muscularis glycine receptors were investigated by immunohistochemistry. Gastrointestinal motility was assessed by in vivo transit distribution histograms with calculated geometric center analysis and jejunal circular smooth muscle contractility in a standard organ bath. The impact of glycine on the muscularis inflammatory responses to surgical manipulation of the intestine were measured by real-time PCR, nitric oxide Griess reaction, prostaglandin ELISA, Luminex and histochemistry. KEY RESULTS: Glycine-gated chloride channels were immunohistochemically localized to muscularis macrophages and postoperative infiltrating leukocytes. Preoperative glycine treatment significantly improved postoperative gastrointestinal transit and jejunal circular muscle contractility. Preoperative glycine injection significantly reduced the induction of interleukin-6 (IL-6), tumor necrosis factor-α, inducible nitric oxide synthase and intercellular adhesion molecule-1 mRNAs, which was associated with the attenuation in postoperative leukocyte recruitment. Nitric oxide and prostanoid release from the postsurgical inflamed muscularis was diminished by glycine. The secretion of the inflammatory proteins IL-6, monocyte chemotactic protein-1/chemokine ligand 2 and macrophage inflammatory protein-1α/chemokine ligand 3 were also significantly decreased by glycine pretreatment. CONCLUSIONS & INFERENCES: The data indicate that preoperative glycine reduces postoperative ileus via the early attenuation of primal inflammatory events within the surgically manipulated gut wall. Therapeutic modulation of resident macrophages by glycine is a potential novel pharmacological target for the prevention of postoperative ileus.

Membrane TLR signaling mechanisms in the gastrointestinal tract during sepsis.

Our bacterial residents are deadly Janus-faced indwellers that can lead to a sepsis-induced systemic inflammatory response syndrome and multiple organ failure. Over half of ICU patients suffer from infections and sepsis remains one of the top 10 causes of death worldwide. Severe ileus frequently accompanies sepsis setting up an insidious cycle of gut-derived microbial translocation and the copious intestinal production of potent systemic inflammatory mediators. Few therapeutic advances have occurred to prevent/treat the sequelae of sepsis. Here, we selectively review studies on cellular membrane-bound Toll-like receptor (TLR) mechanisms of ileus. Virtually, no data exist on Gram-positive/TLR2 signaling mechanisms of ileus; however, TLR2 is highly inducible by numerous inflammatory mediators and studies using clinically relevant scenarios of Gram-positive sepsis are needed. Specific Gram-negative/TLR4 signaling pathways are being elucidated using a 'reverse engineering' approach, which has revealed that endotoxin-induced ileus is dually mediated by classical leukocyte signaling and by a MyD88-dependent non-bone marrow-derived mechanism, but the specific roles of individual cell populations are still unknown. Like TLR2, little is also know of the role of flagellin/TLR5 signaling in ileus. But, much can be learned by understanding TLR signaling in other systems. Clearly, the use of polymicrobial models provides important clinical relevancy, but the simultaneous activation of virtually all pattern recognition receptors makes it impossible to discretely study specific pathways. We believe that the dissection of individual TLR pathways within the gastrointestinal tract, which can then be intelligently reassembled in a meaningful manner, will provide insight into treatments for sepsis.

Role of interleukin 10 in murine postoperative ileus.

BACKGROUND AND AIMS: Intestinal manipulation triggers an inflammatory cascade within the muscularis causing postoperative ileus (POI). The aim of this study was to investigate the recovery and therapeutic potential of interleukin 10 (IL10) for POI. METHODS: POI was induced by bowel surgical manipulation (SM) in wild-type, IL10(-/-) and recombinant murine IL10 (rmIL10)-treated mice. Immunohistochemistry localised IL10 in the muscularis externa, histochemistry quantified neutrophil recruitment, and quantitative PCR quantified alterations in mRNA. Luminex multiplex analysis, Griess reaction and ELISA measured proteins, nitric oxide (NO) and prostanoid release from the muscularis externa, respectively, in 24 h organ culture. Gastrointestinal transit and jejunal circular muscle organ bath techniques assessed gastrointestinal function. RESULTS: In IL10 knockouts compared with the wild type, the expression of numerous proinflammatory mRNAs (IL6, IL1 beta, chemokine C-C motif ligand 2 (CCL2) and haem oxygenase-1) and proteins (IL6, IL1 alpha, IL12, IL17, interferon gamma, tumour necrosis factor alpha, CCL2, interferon-inducible protein-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) were accentuated, and release of muscle inhibitors NO and prostanoids was increased; motility never recovered from manipulation and mortality rate was 87.5%. In wild types, complete functional recovery occurred in 7 days with no mortality. SM delay in transit and suppression in jejunal circular muscle contractions were significantly improved by rmIL10 treatment. Upregulation in IL1 beta, IL6 and CCL2 mRNAs and inflammatory mediators (IL1 alpha, IL6, CCL2, macrophage inflammatory protein-1 alpha, GM-CSF, NO and prostaglandin) after SM were significantly less with rmIL10 treatment, which resulted in a decrease in neutrophil recruitment compared with SM controls. CONCLUSION: IL10 plays an obligatory role in postoperative intestinal recovery, and exogenous IL10 prevents its development. Pre-emptive exogenous recombinant human IL10 could be a treatment for the prevention of clinical POI.

IL-10 administration attenuates pulmonary neutrophil infiltration and alters pulmonary iNOS activation following hemorrhagic shock.

OBJECTIVE AND DESIGN: Several studies report immuno-modulatory effects of endogenous IL-10 after trauma. This study investigates the effect of IL-10 administration on systemic and pulmonary inflammation in hemorrhagic shock. MATERIAL AND METHODS: Male C57/BL6 mice (4-6 animals per group) were subjected to volume controlled hemorrhagic shock for 3 hrs followed by resuscitation. Animals were either subcutaneously injected with 0.9 % saline (Shock group) or with recombinant mouse IL-10 (Shock+IL-10 group) 1 h before and 1 h after the induction of hemorrhagic shock. Serum TNF-alpha, IL-6, and keratinocyte (KC) concentrations were measured with the Luminex multiplexing platform. Acute pulmonary inflammation was assessed by pulmonary myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activity. RESULTS: IL-10 administration significantly decreased serum TNF-alpha (10.30 +/- 1.68 vs 37.42 +/- 10.64; p < 0.05), IL-6 (44.22 +/- 6.65 vs 85.24 +/- 7.94; p < 0.05), and KC (276.74 +/- 52.67 vs 465.61 +/- 58.98; p < 0.05) levels following hemorrhagic shock. Further, pulmonary MPO activity was significantly lower (2698.85 +/- 431.10 vs 4580.67 +/- 294.38; p < 0.05) and pulmonary iNOS activity upregulated. CONCLUSION: These findings suggest that administration of IL-10 modulates the degree of hemorrhage-induced systemic and pulmonary inflammation and support the notion of a central role for iNOS in acute lung injury.

Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury.

Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL-1 beta, IL-6 and TNF-alpha were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air-treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.

Mentation on the immunological modulation of gastrointestinal motility.

The immunological modulation of gastrointestinal motility is currently one of the most dynamic and fascinating areas of enteric research, as investigators are beginning to focus their studies on the pathophysiology of various gastrointestinal dysmotilities. The new fruits of this investigative initiative has resulted in the appearance of a fascinating series of articles which demonstrate that intestinal inflammatory events alter a distinct population of enteric neurons and that these alterations last long past the apparent resolution of the inciting event. Studies over the past few years have unequivocally demonstrated that the muscularis externa itself is an active and complex immunological compartment with unique features. The rodent muscularis externa is constitutively populated by a dense network of muscularis macrophages throughout the entire gastrointestinal tract. Although few other leukocytes are present in the rodent, the human muscularis is densely populated by both macrophages and mast cells. Postoperative ileus and endotoxin-induced ileus have turned out to be extremely useful rodent models to elucidate the importance of muscularis leukocytes in causing intestinal dysfunction. Using models of ileus, studies have demonstrated that a complex molecular inflammatory scenario is triggered within the muscularis externa, which consists of MAP kinase phosphorylation, transcriptior factor activation and the subsequent induction of various cytokines, chemokines and, importantly, smooth muscle inhibitory substances, such as nitric oxide and prostaglandins from iNOS and COX-2. This local molecular inflammatory milieu leads to leukocyte extravasation. Data suggests that the muscularis macrophage network is the conductor of the molecular and cellular inflammatory responses which causes ileus.

Alvimopan and COX-2 inhibition reverse opioid and inflammatory components of postoperative ileus.

Our objective was to investigate the therapeutic potential of peripheral opioid antagonism with alvimopan and anti-inflammatory cyclooxygenase 2 (COX-2) inhibition in an animal model of postoperative ileus with pain management. Intestinal manipulation was conducted in mice and rats with or without postoperative morphine injection. Rodents were orally fed non-digestible fluorescein (FITC)-labelled dextran and transit measured after a period of 90 min. The immunomodulatory effects of morphine and alvimopan were determined on nitric oxide released from the organ cultured muscularis externa. Surgical manipulation of the intestine resulted in a delay in gastrointestinal transit after 24 h that worsened with exogenous morphine. Alvimopan did not significantly alter transit of control or manipulated animals, but significantly antagonized the transit delaying effects of morphine. However, when the inflammatory component was robust enough to obscure a further opioid induced delay in gastrointestinal transit, alvimopan ceased to be effective in improving postoperative intestinal function. Cyclooxygenase 2 inhibition significantly diminished the inflammatory component of postoperative ileus. Surgical manipulation resulted in an increased release of nitric oxide from the inflamed isolated muscularis externa in 24-h organ culture which was not altered by morphine or alvimopan. Two distinct mechanisms exist which participate in postoperative bowel dysfunction: a local inflammatory response which is antagonized by COX-2 inhibition, and a morphine-induced alteration in neural function which can be blocked with alvimopan.

The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis.

Familial lentiginosis syndromes cover a wide phenotypic spectrum ranging from a benign inherited predisposition to develop cutaneous lentigines unassociated with systemic disease, to associations with several syndromes carrying increased risk of formation of hamartomas, hyperplasias, and other neoplasms. The molecular pathways involved in the aetiology of these syndromes have recently been more clearly defined and several major cellular signalling pathways are probably involved: the protein kinase A (PKA) pathway in Carney complex (CNC), the Ras/Erk MAP kinase pathway in LEOPARD/Noonan syndromes, and the mammalian target of rapamycin pathway (mTOR) in Peutz-Jeghers syndrome and the diseases caused by PTEN mutations. Here we discuss the clinical presentation of these disorders and discuss the molecular mechanisms involved. The presence of lentigines in these diseases caused by diverse molecular defects is probably more than an associated clinical feature and likely reflects cross talk and convergence of signalling pathways of central importance to embryogenesis, neural crest differentiation, and end-organ growth and function of a broad range of tissues including those of the endocrine, reproductive, gastrointestinal, cardiac, and integument systems.

A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.

BACKGROUND: Inactivation of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours. METHODS AND RESULTS: A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and non-dexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes. CONCLUSION: We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIalpha as a candidate tumour suppressor gene.

Mechanisms of postoperative ileus.

Postoperative ileus is an iatrogenic condition that follows abdominal surgery. Three main mechanisms are involved in its causation, namely neurogenic, inflammatory and pharmacological mechanisms. In the acute postoperative phase, mainly spinal and supraspinal adrenergic and non-adrenergic pathways are activated. Recent studies, however, show that the prolonged phase of postoperative ileus is caused by an enteric molecular inflammatory response and the subsequent recruitment of leucocytes into the muscularis of the intestinal segments manipulated during surgery. This inflammation impairs local neuromuscular function and activates neurogenic inhibitory pathways, inhibiting motility of the entire gastrointestinal tract. The mechanisms underlying the recruitment of the inflammatory cells, and their interaction with the intestinal afferent innervation, are discussed. Finally, opioids administered for postoperative pain control also contribute to a large extent to the reduction in propulsive gastrointestinal motility observed after abdominal surgery.

Role of vasoactive intestinal peptide and inflammatory mediators in enteric neuronal plasticity.

Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and extrinsic neurones achieve nervous control of digestive functions. The ENS is comprised of many functionally different types of neurons: sensory neurons, interneurons and secreto-motor neurons. Each neuronal population is required to manifest local reflex behavior and is central to the regulation of both motor and secretory activities. It must be emphasized, however, that not only muscle and secretory cells but also other intestinal cells are targeted by enteric neurones, i.e. endocrine cells, interstitial cells of Cajal, immune cells, blood vessels and enteric glia. In addition to the ENS the gastrointestinal tract receives an extrinsic innervation by sympathetic, parasympathetic and sensory fibres. Neuronal projections from the intestine to prevertebral ganglia also exist. Taken together, the picture of a complex nervous regulation of digestive functions highly integrated with the central nervous system and the rest of the autonomic nervous system has emerged. The ENS is adaptive and plastic, but also vulnerable, system and ENS disturbances may be of pathogenic importance in functional bowel disease. In particular the interplay between the enteric neurones and the immune cells is suggested to be of crucial importance. The review discusses possible roles of the mediators vasoactive intestinal peptide (VIP) and prostanoids in ENS plasticity in response to injury and inflammation.

Immunomodulatory effects of inhaled carbon monoxide on rat syngeneic small bowel graft motility.

BACKGROUND: Intestinal transplantation provokes an intense inflammatory response within the graft muscularis that causes intestinal ileus. We hypothesised that endogenously produced anti-inflammatory substances could be utilised as novel therapeutics. Therefore, we tested the protective effects of inhaled carbon monoxide (CO) and an endogenous haeme oxygenase 1 (HO-1) anti-inflammatory mediator on transplant induced inflammatory responses and intestinal ileus in the rat. METHODS: Gastrointestinal transit of non-absorbable FITC labelled dextran and in vitro jejunal circular muscle contractions were measured in controls and syngeneic orthotopic transplanted animals with and without CO inhalation (250 ppm for 25 hours). Inflammatory mRNAs for interleukin (IL)-6, IL-1beta, tumour necrosis factor alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide (iNOS), cyclooxygenase 2 (COX-2), and IL-10 were quantified by real time reverse transcriptase-polymerase chain reaction and HO-1 by northern blot. Histochemical stains characterised neutrophil infiltration and enterocyte apoptosis. RESULTS: Transplantation delayed transit and suppressed jejunal circular muscle contractility. Transplantation induced dysmotility was significantly improved by CO inhalation. Transplantation initiated a significant upregulation in IL-6, IL-1beta, TNF-alpha, ICAM-1, iNOS, COX-2, and HO-1 mRNAs with the graft muscularis. CO inhalation significantly decreased expression of IL-6, IL-1beta, iNOS, and COX-2 mRNAs. CO also significantly decreased serum nitrite levels (iNOS activity). CONCLUSIONS: CO inhalation significantly improved post-transplant motility and attenuated the inflammatory cytokine milieu in the syngeneic rat transplant model. Thus clinically providing CO, the end product of the anti-inflammatory HO-1 pathway, may prove to be an effective therapeutic adjunct for clinical small bowel transplantation.

COX-2 dependent inflammation increases spinal Fos expression during rodent postoperative ileus.

BACKGROUND AND AIMS: Cyclooxygenase 2 (COX-2) and prostaglandins (PGs) participate in the pathogenesis of inflammatory postoperative ileus. We sought to determine whether the emerging neuronal modulator COX-2 plays a significant role in primary afferent activation during postoperative ileus using spinal Fos expression as a marker. METHODS: Rats, and COX-2(+/+) and COX-2(-/-) mice underwent simple intestinal manipulation. The effect of intestinal manipulation on Fos immunoreactivity (IR) in the L(5)-S(1) spinal cord, in situ circumference, and postoperative leucocytic infiltrate of the intestinal muscularis was measured. Postoperative PGE(2) production was measured in peritoneal lavage fluid. The dependence of these parameters on COX-2 was studied in pharmacological (DFU, Merck- Frosst, selective COX-2 inhibitor) and genetic (COX-2(-/-) mice) models. RESULTS: Postoperative Fos IR increased 3.7-fold in rats and 2.2-fold in mice. Both muscularis leucocytic infiltrate and the circumference of the muscularis increased significantly in rats and COX-2(+/+) mice postoperatively, indicating dilating ileus. Surgical manipulation markedly increased PGE(2) levels in the peritoneal cavity. DFU pretreatment and the genetic absence of COX-2(-/-) prevented dilating ileus, and leucocytic infiltrate was diminished by 40% with DFU and by 54% in COX-2(-/-) mice. DFU reversed postsurgical intra- abdominal PGE(2) levels to normal. Fos IR after intestinal manipulation was attenuated by approximately 50% in DFU treated rats and in COX-2(-/-) mice. CONCLUSIONS: Postoperatively, small bowel manipulation causes a significant and prolonged increase in spinal Fos expression, suggesting prolonged primary afferent activation. COX-2 plays a key role in this response. This activation of primary afferents may subsequently initiate inhibitory motor reflexes to the gut, contributing to postoperative ileus.