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.

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 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.

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.

Leukocytes of the intestinal muscularis: their phenotype and isolation.

The basal presence of immunologically potent cells within the intestinal muscularis externa and their functional significance is unclear. Our aim was to investigate the basal distribution of various leukocyte populations within the rat jejunal muscularis. In addition, we sought to immunohistochemically phenotype the muscularis macrophage in jejunal whole-mounts, isolate these cells in primary culture, and investigate their ontogenesis. Macrophages form a regularly distributed network that expresses major histocompatibility complex class II, CD14 receptors, and a low level of CD11/CD18. The macrophages are activated by dissection and are present in fetal animals. Enriched macrophage cultures show a normal resident phenotype and remain present for weeks in dissociated muscularis cultures. The results also demonstrate the presence of neutrophils, monocytes, mast cells, and lymphocytes within the muscularis and suggest that the dense network of muscularis macrophages may be a potent resident trigger for inflammation in response to tissue injury or bacterial translocation.

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.

Molecular and functional contractile sequelae of rat intestinal ischemia/reperfusion injury.

BACKGROUND: Pathophysiological states that produce intestinal ischemia/reperfusion injury (I/R) initiate an inflammatory cascade and cause ileus. The aims of this study were to investigate the local cellular responses and molecular mechanisms, which contribute to intestinal dysmotility after selective intestinal I/R injury. METHODS: ACI rats were subjected to 75 min SMA clamp-induced ischemia followed by reperfusion and were killed at 0 min, 30 min, and 24 hr. Whole mounts of the jejunum were used to immunohistochemically quantify alterations in leukocytes, and circular muscle strips were used to assess organ bath muscle function. Muscularis and mucosa extracts were isolated from the intestine and used for reverse transcription assisted polymerase chain reaction mRNA measurements of granulocyte-colony stimulating factor and interleukin-6, and for determination of nuclear factor kappa B and Stat3 activation. RESULTS: Intestinal I/R injury resulted in the significant recruitment of neutrophils and monocytes into the intestinal muscularis and a functional suppression in jejunal circular muscle contractions. These I/R injury induced cellular responses were preceded by the molecular activation of nuclear factor kappa B, up-regulation of granulocyte colony-stimulating factor and interleukin-6 mRNA and phosphorylation of the downstream signaling and transcription factor Stat3. CONCLUSIONS: I/R injury evokes a molecular and cellular inflammatory response within the intestinal muscularis that is associated with a subsequent decrease in intestinal motility.

Functional impairment of enteric smooth muscle and nerves caused by chronic intestinal allograft rejection regresses after FK506 rescue.

We have previously demonstrated that subclinical chronic rejection (CR) induces structural and functional alterations in enteric smooth muscle and nerves in a rat model of small intestinal transplantation. This study was designed to investigate the effect of prolonged FK506 rescue therapy on these sequelae of CR. Immunohistochemistry of BrdU-labeled muscle cells demonstrated that active proliferation of intestinal smooth muscle caused by CR was successfully aborted by FK506 rescue therapy after a period of 30 days (control = 0.14 +/- 0.09; CR = 30.4 +/- 1.73; rescue = 2.4 +/- 0.63 cells/jejunal cross-section, P < 0.01). However, FK506 did not reverse the already established increase in muscular thickness (control = 92 +/- 2.4; CR = 193 +/- 10.6; rescue = 188 +/- 8.1 microns) due to CR. Bethanechol stimulated circular muscle contractility was improved markedly with rescue therapy (maximal contractile force reached 39.5% of control values in CR grafts and 68.8% after rescue). Rescue therapy did not reverse the loss of NADPH-diaphorase positive myenteric ganglia (control = 37 +/- 1.4; CR = 28 +/- 2.9; rescue = 23 +/- 1.7 ganglia/cross-section). Despite the persistent loss of ganglia, inhibitory junction potentials (IJPs) improved significantly returning to control values with FK506 (control = 10 +/- 0.5; CR = 5 +/- 0.3; CR rescue = 10 +/- 0.7 mV; IJPs recorded at 1 pulse/150V/0.75 ms). Although structural changes in enteric smooth muscle and myenteric neurons induced by CR were not reversed, the progression of subclinical CR can be effectively curbed by FK506 rescue therapy. The improvement in muscular mechanics and inhibitory neural innervation is probably due to the cessation of infiltrating immunocytes and sprouting of remaining myenteric nerves.

Increased expression of interferon-gamma in a rat model of chronic intestinal allograft rejection.

Chronic rejection remains a major cause of late graft dysfunction. Although much research has focused on acute rejection, little is known about the mechanisms of chronic rejection. Our group has recently reported evidence of significant intestinal smooth muscle hypertrophy and hyperplasia associated with abnormal contractile and electrical activities in a rat model of chronic intestinal rejection. The changes in the smooth muscle layer are associated with a significant inflammatory infiltrate. In order to further delineate the immune mechanisms of chronic rejection, we sought to clarify the nature of this infiltrate. Orthotopic small bowel transplantation was performed using an allogeneic (ACI-Lewis) rat combination. The rats only received immunosuppression for the first 28 days posttransplantation (cyclosporine 15 mg/kg daily from postoperative day 0 to 6 and every other day from postoperative day 7 to 28). This led to chronic rejection of the graft by day 90, at which time the rats were sacrificed. Analysis by immunohistochemistry revealed NK and CD5+ leukocytes infiltrating the muscular layer. Examination of cytokine production by radiolabeled polymerase chain reaction showed high levels of steady state interferon-gamma mRNA in full thickness intestinal segments and within the isolated muscularis of chronically rejecting intestinal allografts as compared to syngeneic and control grafts. Interferon-gamma mRNA was localized to both the muscularis and mucosa. Interestingly, positively hybridized cells within the muscularis tended to preferentially localize to the myenteric and submucosal plexuses suggesting potential role for this cytokine in chronic intestinal ejection.

Heterotopic intestinal transplantation aggravates the insult of chronic rejection.

BACKGROUND: Intestinal grafts are placed either heterotopically (out of continuity) or orthotopically (in continuity); the latter is believed to be advantageous, as intraluminal nutrients and intestinal secretions might modulate the intestinal immune status and possibly delay rejection. METHODS: This study was designed to delineate the effects of heterotopic versus orthotopic allograft position on the morphology and function of intestinal smooth muscle in our rat model of chronic rejection. Syngeneic orthotopic grafts were evaluated to control for changes due to the transplantation process. RESULTS: Histochemistry of the graft's muscularis externa showed a significant thickening due to hyperplasia and hypertrophy, which was most pronounced in heterotopic grafts (control = 92+/-2.4 microm, syngeneic grafts = 140+/-6.7 microm, orthotopic allografts = 278+/-26.6 microm, heterotopic allografts = 456+/-50 microm). In terms of function, muscle strips from allografts only generated 23% of the total bethanechol-induced contractile force in vitro compared to unoperated controls and syngeneic grafts. The mean resting membrane potential of control and isograft muscle cells was -69 +/- 0.9 mV with a slow-wave amplitude of 20+/-0.5 mV. Chronic rejection hyperpolarized the resting membrane potential of orthotopic allografts (-66 +/- 0.5 mV) and even more so of heterotopic allografts (-58 +/- 3.4 mV). Slow-wave amplitudes were decreased in orthotopic (14+/-0.9 mV) and nearly abolished in heterotopic allografts (2+/-1.2 mV). CONCLUSIONS: Our data indicate that allografts in heterotopic position are most susceptible to the insult of chronic rejection exemplified by increased proliferative and hypertrophic transformation of intestinal smooth muscle and a marked decrease in mechanical and electrical activity.

The effect of small bowel transplantation on the morphology and physiology of intestinal muscle: a comparison of autografts versus allografts in dogs.

The effects of acute (AR) and chronic rejection (CR) on intestinal smooth muscle that are responsible for the dysmotility following small bowel transplantation (SBTX) are incompletely understood. Jejunal and ileal specimens from normal control dogs (n=7), and autotransplanted dogs were examined at 7 days (n=6) and 1 (n=7), 3 (n=6), 6 (n=6), and 12 months (n=6). Allotransplanted dogs that developed AR (n=8) and CR (n=5) were examined for gross and microscopic morphology (muscle thickness, the number and size of myocytes, and inflammatory infiltrate), and for contractile and intracellular electrical function in vitro. Auto-SBTX did not alter morphology at any period, but contractile function was impaired at 7 days (73.6%) compared with normal intestine. Acute rejection did not influence myocyte number or size, but was associated with a prominent infiltrate of neutrophils and lymphocytes, and severely impaired contractile function (20.6%) compared with auto-SBTX controls. Acute rejection also significantly inhibited the amplitude of slow waves and of inhibitory junction potentials. Chronic rejection caused thickening of muscularis propria by both hyperplasia (175.5%) and hypertrophy (202.6%) accompanied by moderate inflammatory cell infiltrate compared with auto-SBTX controls. We conclude that the marked inflammatory infiltrate into the muscularis propria indicates that the graft muscle is injured by both acute and chronic rejection; impaired function of intestinal smooth muscle following SBTX results from both rejection and the injury associated with transplantation, and chronic rejection following SBTX is associated with both hyperplasia and hypertrophy of the muscularis propria.

Review article: effects of the 5-HT3 receptor antagonist alosetron on neuromuscular transmission in canine and human intestinal muscle.

BACKGROUND: Currently, therapeutic treatments for irritable bowel syndrome fail to produce significant clinical results. We hypothesized that alosetron, a selective 5-HT3 antagonist, may provide symptomatic relief in irritable bowel syndrome patients through a decrease in the amplitude of gastrointestinal contractions. AIM: To determine the in vitro effect of alosetron on neuromuscular transmission in the canine and human jejunal and colonic muscularis externa. RESULTS: Alosetron diminished electrical field-stimulated (EFS) contractions recorded from muscles of the canine and human small and large intestines. Mechanistically, the diminished EFS response could be explained by the ability of alosetron to decrease the fractional release of 14C-choline radiolabelled acetylcholine evoked by EFS from human jejunal muscle. The inhibition of EFS contractions was not limited to atropine-sensitive events, as non-cholinergic excitatory EFS evoked contractions were also inhibited. Additionally, alosetron at high concentrations (> 30 microM) directly altered bethanechol stimulated contractions. CONCLUSION: Caution must be used in the interpretation of these data because significant alterations in EFS-induced contractions were only observed with large pharmacological concentrations of alosetron, and the response was not selective for cholinergically-mediated excitatory neuromuscular transmission.

Small bowel transplantation and chronic rejection alter rat intestinal smooth muscle structure and function.

BACKGROUND: The purpose of this study was to determine whether morphologic and functional changes in intestinal smooth muscle occur after small bowel transplantation (SBTx) and during chronic rejection. METHODS: Orthotopic SBTx was performed in syngeneic (ACI-ACI, n = 6) and allogeneic (ACI-Lewis, n = 6) rat strain combinations. The latter received temporary immunosuppression (cyclosporine 15 mg/kg/body weight on postoperative days 0 to 6 once a day, postoperative days 7 to 28 every other day), which led to clinically quiescent chronic rejection of the graft by 90 days after SBTx. At that time structure and function of the jejunal muscularis externa were evaluated with histochemistry, mechanical organ bath, and intracellular electrical recording techniques. RESULTS: Histochemistry showed a 1.5-fold thickening of the intestinal muscularis externa of syngeneic grafts, although contractile properties and intracellular electrical activity were not significantly different from controls. Allogeneic, chronically rejecting grafts showed a threefold increase in the thickness of the muscularis externa as a result of both smooth muscle hyperplasia and hypertrophy. Muscle strips from chronically rejecting grafts generated only 23% of the maximal contractile force generated by controls (bethanechol 300 mumol/L). Median effective concentration and threshold values were not significantly different. Intracellular electrical activity of circular smooth muscle cells revealed a significantly more depolarized resting membrane potential and a reduction in slow wave amplitude compared with controls. CONCLUSIONS: Syngeneic SBTx resulted in a significant thickening of the muscularis externa with an apparent adaptation to control in vitro physiologic function. Allogeneic SBTx subject to chronic rejection leads to profound morphologic changes and functional impairments. Changes in muscle structure and function evolve before the clinical signs of graft rejection.

Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in rat.

BACKGROUND: Surgical manipulation of the intestine results in the massive movement of leukocytes into the intestinal muscularis at 24 hours. This is associated with muscle inhibition. The aim of this study was to temporally associate leukocyte extravasation with ileus after surgical manipulation. METHODS: Rats underwent a simple manipulation of the small bowel and were killed at various times (0, 0.25, 0.5, 1, 3, 6, 12, and 24 hours) postoperatively. Jejunal circular-muscle contractile activity was assessed in a standard organ bath. Both extravasating and resident leukocytes were immunohistochemically stained in muscularis whole mounts. RESULTS: Contractile activity was significantly reduced immediately after surgery, but rapidly returned to control levels at 3 hours. After recovery, muscle function decreased at 12 and 24 hours (41% and 81%, respectively). The resident muscularis macrophage network demonstrated cellular activation 1 hour postoperatively. The number of leukocytes increased over time (neutrophils, 67.5-fold; monocytes, 98.2-fold; and mast cells, 47-fold at 24 hours). CONCLUSIONS: The functional results demonstrate a biphasic response in the suppression of muscle activity after surgical manipulation. Regression analysis (r2 = 0.998) of the temporal development of leukocyte infiltration and the protracted phase of muscle inhibition provides evidence for a correlation between cellular inflammation and postoperative dysmotility.

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.

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.

Electrical basis for the effects of ethyl alcohol on canine gastric corpus muscles.

The effects of ethyl alcohol (EtOH) on membrane potential and slow wave activity were tested in strips of canine corpus circular muscle. Previous studies have shown that EtOH (0.1-1%) reduced the force and frequency of phasic contractions of corpus muscles and increased tone. It was the intention of this study to determine whether the mechanical effects were due to an electrical mechanism. Intracellular recordings revealed that EtOH hyperpolarized resting membrane potential and reduced the amplitude, duration and frequency of slow waves. These changes were concentration-dependent over the same range of EtOH concentrations that inhibited phasic mechanism activity. Simultaneous recordings of force and membrane potential demonstrated these effects. The tone produced by corpus muscles exposed to EtOH could not be explained by an electrical mechanism. The fact that membrane potential and several parameters of the slow wave depolarization are affected by EtOH might be explained by an increase in membrane conductance produced by EtOH.