Severity of complications following restorative proctocolectomy in children is related to staging not diagnosis.

BACKGROUND: Restorative proctocolectomy (RPC) is performed using a variety of staged procedures for several diseases. Our aim was to assess whether the severity of complications, classified according to Clavien-Dindo, was related to the diagnosis or the procedure. METHODS: A consecutive series of children receiving an ileoanal pouch was prospectively recorded. Complications were scored by two blinded observers. Major complications were Clavien-Dindo ≥3b. Procedures were classified as: colectomy, proctectomy and pouch or proctocolectomy and pouch. Diagnoses were classified as: ulcerative colitis, familial adenomatous polyposis or other: idiopathic constipation, total colonic Hirschsprung's disease, juvenile polyposis, Crohn's colitis, fibrosing colonopathy or necrotising enterocolitis. RESULTS: 128 children underwent 191 procedures: 61 colectomies, 63 proctectomies and 67 proctocolectomies. 84 children had ulcerative colitis, 20 had FAP and 24 had other indications. Major complications were significantly more likely with proctocolectomy (16/67, 24%) than with either colectomy (4/61, 7%) or proctectomy (8/63, 13%), p = 0.01. There was no association between diagnosis and major complications: ulcerative colitis (18/133, 14%), FAP (5/20, 25%), other (5/38, 13%) p = 0.4. There was no increase in major complications following proctectomy if a major complication had occurred during prior colectomy. Overall, 15% of procedures experienced a major complication. 6/9 stoma related complications required operative intervention. CONCLUSIONS: The severity of complications after RPC in children is related to use of a two stage rather than three stage sequence of surgery, not the underlying diagnosis. TYPE OF STUDY: Case control study. LEVEL OF EVIDENCE: Level III.

Oncostatin M is expressed in atherosclerotic lesions: a role for Oncostatin M in the pathogenesis of atherosclerosis.

OBJECTIVE: Chronic inflammation plays a pivotal role in the development and progression of atherosclerosis. The inflammatory response is mediated by cytokines. The aim of this study was to determine if Oncostatin M (OSM), a monocyte and T-lymphocyte specific cytokine is present in atherosclerotic lesions. We also investigated the roles of signal transducer and activator of transcription (STAT)-1 and STAT-3 in regulating OSM-induced smooth muscle cell (SMC) proliferation, migration and cellular fibronectin (cFN) synthesis. METHODS AND RESULTS: Immunostaining of atherosclerotic lesions from human carotid plaques demonstrated the expression of OSM antigen in both macrophages and SMCs. Explanted SMCs from human carotid plaques expressed OSM mRNA and protein as determined by RT-PCR and Western blotting. Using the chow-fed ApoE(-/-) mouse model of atherosclerosis, we observed that OSM was initially expressed in the intima at 20 weeks of age. By 30 weeks, OSM was expressed in both the intima and media. In vitro studies show that OSM promotes SMC proliferation, migration and cFN synthesis. Lentivirus mediated-inhibition of STAT-1 and STAT-3 prevented OSM-induced SMC proliferation, migration and cellular fibronectin synthesis. CONCLUSIONS: These findings demonstrate that OSM is expressed in atherosclerotic lesions and may contribute to the progression of atherosclerosis by promoting SMC proliferation, migration and extracellular matrix protein synthesis through the STAT pathway.

Management of gastroesophageal reflux associated with malrotation in children.

AIM: Children being investigated for gastroesophageal reflux (GOR) have a high incidence of malrotation. Current literature suggests these patients should be managed with a combined antireflux and Ladd's procedure. We review our experience, the largest series to date, of performing an elective Ladd's procedure as the first-line intervention. METHOD: Retrospective case note review of 20 children with significant symptoms of GOR and an incidental finding of malrotation. Children presenting immediately with bilious vomiting were excluded. All patients underwent a Ladd's procedure as their sole primary operative intervention. RESULTS: Median age at operation was 7 months (21 days-12 years). Fifteen patients (75%) had evidence of reflux on barium contrast study. All children were followed up for at least 6 months. Eighteen (90%) had resolution or significant improvement of their symptoms postsurgery. Only 3 have not managed to tolerate a full oral diet, all unrelated to GOR. None of our series required an antireflux procedure. CONCLUSION: In children with debilitating vomiting necessitating surgical management, a contrast study is imperative in the work up. The high incidence of GOR and the significant improvement after correction of malrotation show the relationship between delayed gastric emptying and GOR. We suggest that when an abnormally placed duodenojejunal flexure is found, a Ladd's procedure alone is sufficient and may obviate the need for a more invasive antireflux procedure.

Sucrose co-administration reduces the toxic effect of lectin on gut permeability and intestinal bacterial colonization.

INTRODUCTION: Legume lectins can have toxic effects when consumed without adequate cooking, occasionally leading to an acute gastroenteritis. Lectins are sugar binging proteins and may use this property to execute their toxic effects; these toxic effects may be secondary to increased gut bacteria and intestinal permeability. However, whether or not sucrose rescues these toxic effects by decreasing gut bacterial concentration and intestinal permeability is unknown. AIM: Our aim was to test the hypothesis that sucrose may reduce toxic effects of legume lectins by protecting barrier function, bacterial overgrowth and bacterial translocation. METHODS: Twenty-four rats were randomized to an ad libitum diet of either standard rat chow, a chow containing 26% crude red kidney beans or a chow containing 26% crude red kidney beans supplemented with 1 mM sucrose in drinking water for 24 h. After 12-h fast, rats were gavaged with sugar probes; breath gas and urine were collected for 5 h. Intestine and liver tissues were then collected. Mucosa-associated total bacterial count were measured by targeting the 16s rRNA gene. Four groups of in vitro Caco-2 cell lines were treated with PBS, 200 µg/ml phytohemagglutinin (PHA), 1 mM sucrose and both 200 µg/ml PHA and 1 mM sucrose, respectively, and trans-epithelial resistance was measured. RESULTS: Rats fed crude red kidney beans for 24 h showed significant weight loss when compared to controls (P < 0.05), as well as increased intestinal permeability (P < 0.05), increased bacterial load (P < 0.05) and increased bacterial translocation to the liver (P < 0.05). Sucrose rescues the drop in trans-epithelial resistance due to PHA in CaCO2-cells (P < 0.05). CONCLUSIONS: Sucrose reduced crude red kidney beans induced increase in intestinal permeability, bacterial load and translocation. Since red kidney beans are an important source of dietary protein in the world, their potential toxicity when inadequately cooked may be rescued by a suitable complementary diet.

Bleeding jejunal phlebectasia in an adolescent: case report.

The first case of jejunal phlebectasia in a pediatric patient presenting with life-threatening gastrointestinal bleeding is described. The pathology of vascular anomalies is discussed.

Solitary pulmonary infantile hemangioma in an infant with atrial septal defect.

Pulmonary infantile hemangiomas are extremely rare in infancy and childhood. We describe a case of a 22-month-old infant who presented with repeated chest infections. Imaging studies revealed a solitary parenchymal lung lesion in the left upper lobe, an atrial septal defect, and mild right ventricular dilatation. Various investigations failed to delineate the precise nature of the lung lesion and it was resected. Histological examination of the lung lesion showed an infantile hemangioma, which expressed glucose transporter-1 protein, GLUT-1, a marker of infantile hemangiomas. This case represents a unique coexistence of 2 lesions, both of which resulted in right-sided overload, contributed to mainly by the atrial septal defect causing increased volume and, to a lesser extent, by the pulmonary hemangioma resulting in increased pressure. This case also emphasizes the fact that infantile hemangioma, although rare, should be considered as a differential diagnosis of solitary lung lesions.

Therapeutic potential of novel modulators of neovascularization.

Neovacularization is an important biological process whereby new blood vessels develop in both health and disease. During development, blood vessels are formed from mesodermal cells in a process called vasculogenesis. The vascular network then expands by the sprouting of new vessel networks from pre-established vessels in a process known as angiogenesis. However, in adult life, undesirable neovascularization is associated with tumor development and a growing list of 'angiogenesis-dependent' diseases, including cardiovascular complications. Furthermore, diseases characterized by ischemia-induced tissue damage cause a neovascularization response to facilitate tissue repair. Recent research has identified novel molecular and cellular mediators of neovascularization that, in adult life, recapitulate angiogenic processes observed during embryonic development. The discovery of vascular progenitor cells and new molecules that display selective functions in modulating endothelial cell fate, migration and patterning, vessel morphogenesis and the amplification of angiogenic signaling by regulating the master signal VEGF, opens the door to new clinical strategies that target angiogenesis-dependent diseases or that can promote therapeutic neovascularization.

An initial experience of 100 paediatric laparoscopic nephrectomies with transperitoneal or posterior prone retroperitoneoscopic approach.

The objective of this study was to evaluate the outcome of the initial 100 consecutive laparoscopic nephrectomies using a transperitoneal or a posterior prone retroperitoneoscopic approach. The medical records of 97 consecutive children who underwent laparoscopic nephrectomy between January 2000 and December 2003 were reviewed. Children having concomitant operative procedures were excluded from the study. Laparoscopy was performed by a transperitoneal (TP) or a posterior prone retroperitoneoscopic (PPR) approach based on the preference of the operating surgeon. A total of 100 procedures were successfully completed laparoscopically. Two children required conversion to open surgery. The median operating time was 112 min for the TP approach and 96 min for the PPR approach (P = 0.002). There was no significant difference in the analgesic requirements between the two groups. The rate of complications was similar, as was the length of hospital stay. This was despite the fact that the children in the TP group were somewhat older in age. In children having bilateral native kidney nephrectomy, peritoneal dialysis was successfully established within 48 h after surgery in the PPR group. Taking into account the heterogeneous nature of our group of patients, a reliable conclusion in regard to the difference in operative time, analgesic requirement or approach could not be ascertained. There is the suggestion however, that both the TP and PPR approaches for nephrectomy are equally applicable in children. The posterior prone retroperitoneoscopic approach may have an advantage in children who require peritoneal dialysis.

The "linker" region (amino acids 38-47) of the disintegrin elegantin is a novel inhibitory domain of integrin alpha5beta1-dependent cell adhesion on fibronectin: evidence for the negative regulation of fibronectin synergy site biological activity.

Disintegrins are a family of potent inhibitors of cell-cell and cell-matrix adhesion. In this study we have identified a region of the disintegrin elegantin, termed the "linker domain" (amino acids 38-47), with inhibitory activity toward alpha(5)beta(1)-mediated cell adhesion on fibronectin (Fn). Using a chimeric structure-function approach in which sequences of the functionally distinct disintegrin kistrin were introduced into the elegantin template at targeted sites, a loss of inhibitory function toward alpha(5)beta(1)-mediated adhesion on Fn was observed when the elegantin linker domain was substituted. Subsequent analysis comparing the inhibitory efficacies of the panel of elegantin-kistrin chimeras toward CHO alpha(5) cell adhesion on recombinant Fn III(6-10) fragments showed that the loss of inhibitory activity associated with the disruption of the elegantin linker domain was dependent upon the presence of a functional Fn III(9) synergy site within the Fn III(6-10) substrate. This suggested that the elegantin linker domain inhibits primarily the activity of the Fn synergy domain in promoting alpha(5)beta(1) integrin-mediated cell adhesion. Construction of a cyclic peptide corresponding to the entire region of the elegantin linker domain showed that this domain has intrinsic alpha(5)beta(1) inhibitory activity comparable with the activity of the RGDS peptide. These data demonstrate a novel biological function for a disintegrin domain that antagonizes integrin-mediated cell adhesion.

Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: enhancement of VEGF biological activity by a singular growth factor/matrix protein synergism.

We describe extracellular interactions between fibronectin (Fn) and vascular endothelial growth factor (VEGF) that influence integrin-growth factor receptor crosstalk and cellular responses. In previous work, we found that VEGF bound specifically to fibronectin (Fn) but not vitronectin or collagens. Herein we report that VEGF binds to the heparin-II domain of Fn and that the cell-binding and VEGF-binding domains of Fn, when physically linked, are necessary and sufficient to promote VEGF-induced endothelial cell proliferation, migration, and Erk activation. Using recombinant Fn domains, the C-terminal heparin-II domain of Fn (type III repeats 13 to 14) was identified as a key VEGF-binding site. Mutation of the heparin-binding residues on FnIII(13-14) abolished VEGF binding, and peptides corresponding to the heparin-binding sequences in FnIII(13-14) inhibited VEGF binding to Fn. Fn fragments containing both the alpha5beta1 integrin-binding domain (III 9 to 10) and the VEGF-binding domain (III 13 to 14) significantly enhanced VEGF-induced EC migration and proliferation and induced strong phosphorylation of the VEGF receptor and Erk. Neither the cell-binding or VEGF-binding fragment of Fn alone had comparable VEGF-promoting effects. These results suggest that the mechanism of VEGF/Fn synergism is mediated extracellularly by the formation of a novel VEGF/Fn complex requiring both the cell-binding and VEGF-binding domains linked in a single molecular unit. These data also highlight a new function for the Fn C-terminal heparin-binding domain that may have important implications for angiogenesis and tumor growth.

Novel hepatocyte growth factor (HGF) binding domains on fibronectin and vitronectin coordinate a distinct and amplified Met-integrin induced signalling pathway in endothelial cells.

BACKGROUND: The growth of new blood vessels in adult life requires the initiation of endothelial cell migration and proliferation from pre-existing vessels in addition to the recruitment and differentiation of circulating endothelial progenitor cells. Signals emanating from growth factors and the extracellular matrix are important in regulating these processes. RESULTS: Here we report that fibronectin (FN) and vitronectin (VN) modulate the responses of endothelial cells to HGF (Scatter Factor), an important pro-angiogenic mediator. Novel binding sites for HGF were identified on both FN and VN that generate molecular complexes with enhanced biological activity and these were identified in the supernatants of degranulated platelet suspensions implicating their release and formation in vivo. In the absence of co-stimulation with an ECM glycoprotein, HGF could not promote endothelial cell migration but retained the capacity to induce a proliferative response utilising the Map kinase pathway. Through promoting Met-Integrin association, HGF-FN and HGF-VN complexes coordinated and enhanced endothelial cell migration through activation of the PI-3 kinase pathway involving a Ras-dependent mechanism whereas a Ras-independent and attenuated migratory response was promoted by co-stimulation of cells with HGF and a non-binding partner ECM glycoprotein such as collagen-1. CONCLUSIONS: These studies identify a novel mechanism and pathway of HGF signalling in endothelial cells involving cooperation between Met and integrins in a Ras dependent manner. These findings have implications for the regulation of neovascularization in both health and disease.

Fibronectin promotes VEGF-induced CD34 cell differentiation into endothelial cells.

BACKGROUND: Adult endothelial progenitor cells (EPC) may be a useful source for engineering the endothelialization of vascular grafts. However, the optimal factors that promote differentiation of EPCs into endothelium remain to be elucidated. The goal of this current report was to determine which extracellular matrix (ECM) protein might modulate or enhance the effects of EPCs on differentiation into mature endothelium. METHODS: Human EPCs (CD34(+) cells) were cultured in ECM-coated six-well plates in MCDB-131 medium containing vascular endothelial growth factor (VEGF), insulin-like growth factor-1, and basic fibroblast growth factor. After 21 days, differentiated endothelial colonies were confirmed by immunofluorescence for von Willebrand factor (vWF) and vascular-endothelial (VE)-cadherin and mRNA expression of the endothelial markers Flk-1, vWF, and VE-cadherin. Cell migration toward the VEGF-matrix protein combinations was also measured. RESULTS: As judged by positive staining for endothelial markers vWF and VE-cadherin, the combination of VEGF with fibronectin (FN) produced significantly more endothelial colonies (P <.05) than did collagens I or IV or vitronectin. Defined fragments of FN did not enhance VEGF-mediated effects. Fibrinogen produced intermediate stimulation of differentiation. FN also enhanced VEGF-mediated CD34(+) cell migration. Blockade of alpha5beta1, but not alphavbeta3 or alphavbeta5, inhibited both VEGF-mediated CD34(+) cell differentiation and migration. CONCLUSIONS: VEGF and FN together significantly promote the migration and differentiation of CD34(+) cells. This synergism is specific to FN and the alpha5beta1 integrin. Combinations of VEGF and FN may be useful in promoting differentiation of circulating endothelial progenitors into endothelial cells for tissue engineering. Clinical relevance Treatment of injured or diseased tissues with adult stem cells is a promising approach. In particular, bone marrow derived circulating endothelial progenitors (CEP's) have been shown to differentiate into endothelial cells in vitro and promote tissue revascularization of ischemic limbs and myocardium in vivo. Because of the relative ease of obtaining CEP's and as well as its high proliferative rate, CEP's may have clinical potential for endothelialization of prosthetic vascular grafts and revascularization of injured myocardium. However, there is a need to better understand the molecular pathways involved in the proliferation and differentiation of CEP's to take full advantage of its clinical potential.

Are you ready to become a robo-surgeon?

Robotic and minimally invasive surgery represents the future of modern surgical care. However, its role during the training of surgical residents has yet to be investigated. A previous study conducted by our group surveyed program directors at accredited general surgery training programs in the United States to determine the prevalence and application of robotics in their residency programs. This current study is a follow-up survey sent to residents across the United States to see whether they were being adequately trained and exposed to robotic surgery during their training. A survey was sent to 1800 general surgery residents, and their responses were tabulated and analyzed. Twenty-three per cent of the 1800 residents responded to our survey. An overwhelming 57 per cent of the responders indicated a high interest in robotic surgery. However, 80 per cent of the responders indicated not having a robotic training program. Robotic surgery has led to many promising advancements within the surgical subspecialties. With this emerging technology comes the need for a greater emphasis on the training of surgeons in robotics during their residency.

Use of sarcoma-based chemotherapy in a case of congenital mesoblastic nephroma with liver metastases.

Congenital mesoblastic nephroma was originally considered to be a benign neoplasm. A more aggressive cellular form, however, that has a close relationship to congenital fibrosarcoma, is widely described. Previous reported sites of metastases are the lungs, heart, brain, and bone. We describe a patient with isolated metastasis to liver and review the management, together with evidence that it may be more appropriate to use a vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) regimen rather than Wilm's tumor-based regimens in those cases for which chemotherapy is indicated.

Evidence for a role for Galphai1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Galphai1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder.

We have examined platelet functional responses and characterized a novel signaling defect in the platelets of a patient suffering from a chronic bleeding disorder. Platelet aggregation responses stimulated by weak agonists such as adenosine diphosphate (ADP) and adrenaline were severely impaired. In comparison, both aggregation and dense granule secretion were normal following activation with high doses of collagen, thrombin, or phorbol-12 myristate-13 acetate (PMA). ADP, thrombin, or thromboxane A2 (TxA2) signaling through their respective Gq-coupled receptors was normal as assessed by measuring either mobilization of intracellular calcium, diacylglycerol (DAG) generation, or pleckstrin phosphorylation. In comparison, Gi-mediated signaling induced by either thrombin, ADP, or adrenaline, examined by suppression of forskolin-stimulated rise in cyclic AMP (cAMP) was impaired, indicating dysfunctional Galphai signaling. Immunoblot analysis of platelet membranes with specific antiserum against different Galpha subunits indicated normal levels of Galphai2,Galphai3,Galphaz, and Galphaq in patient platelets. However, the Galphai1level was reduced to 25% of that found in normal platelets. Analysis of platelet cDNA and gDNA revealed no abnormality in either the Galphai1 or Galphai2 gene sequences. Our studies implicate the minor expressed Galphai subtype Galphai1 as having an important role in regulating signaling pathways associated with the activation of alphaIIbbeta3 and subsequent platelet aggregation by weak agonists.

The telecommunication revolution in the medical field: present applications and future perspective.

In the present review, we analyze the achievements of telecommunication innovations in the medical field focusing on patient care and medical-education aspects. In this regard, the telecommunication revolution has offered medical professionals the possibility to transmit information of any sort zeroing transmission time latency and annihilating spatial distances. Although telemedicine is still in its infancy, multiple applications of this science have already been successfully tested. As an example, robotically mediated telesurgery has it made possible for surgeons to operate standing at a considerable distance from the operating table without even touching or directly seeing the surgical field. Moreover, medical education and medical consulting have acquired new and wider ranges of applicability thanks to the introduction of teleproctoring, telementoring, and teleconsulting. Finally, in the very near future, telepresence surgery will permit "virtual" operations on patients where surgeons can project their manual dexterity, psychomotor skills, and problem-solving ability to remote locations. In this context, telemedicine will support a more equal distribution of medical knowledge and promote excellence in patients' care even in the most disadvantaged environments.

Novel vascular endothelial growth factor binding domains of fibronectin enhance vascular endothelial growth factor biological activity.

Interactions between integrins and growth factor receptors play a critical role in the development and healing of the vasculature. This study mapped two binding domains on fibronectin (FN) that modulate the activity of the angiogenic factor, vascular endothelial growth factor (VEGF). Using solid-phase assays and surface plasmon resonance analysis, we identified two novel VEGF binding domains within the N- and C-terminus of the FN molecule. Native FN bound to VEGF enhanced endothelial cell migration and mitogen-activated protein (MAP) kinase activity, but FN that is devoid of the VEGF binding domains failed to do so. Coprecipitation studies confirmed a direct physical association between VEGF receptor-2 (Flk-1) and the FN integrin, alpha5beta1, which required intact FN because FN fragments lacking the VEGF binding domains failed to support receptor association. Thrombin-activated platelets released intact VEGF/FN complexes, which stimulated endothelial cell migration and could be inhibited by soluble high affinity VEGF receptor 1 and antibodies to alpha5beta1 integrin. This study demonstrates that FN is potentially a physiological cofactor for VEGF and provides insights into mechanisms by which growth factor receptors and integrins cooperate to influence cellular behavior.

Sildenafil in the Treatment of SSRI-Induced Sexual Dysfunction: A Pilot Study.

BACKGROUND: Sexual dysfunction is a well-documented side effect of selective serotonin reuptake inhibitors (SSRIs). Commonly reported side effects include erectile impotence, anorgasmia, ejaculatory delay, pain, loss of sensation, and decreased pleasure. Early reports of the reversal of sexual dysfunction after using sildenafil in male and female patients receiving various types and dosages of SSRIs are promising and prompted this study. Our aim was to evaluate the effects of oral sildenafil on reported secondary sexual dysfunction in patients concurrently treated with SSRIs. METHOD: Fourteen male patients who developed sexual dysfunction while receiving SSRIs were screened using the Arizona Sexual Experience (ASEX) scale. An electrocardiogram was obtained at the beginning and at the end of the study. Each patient was prescribed sildenafil tablets to be taken twice a week, 25-100 mg, prior to sexual activity and told to record the findings in a running diary which he was to keep during his treatment period. The patients were seen weekly and evaluated by clinical interview and ASEX scale. Patients were treated for a total of 8 weeks. RESULTS: All but 1 of the 14 patients experienced an improvement of sexual dysfunction, with 9 patients at the first dose of 25 mg and 4 at higher doses (3 at 50 mg and 1 at 75 mg). One patient required 100 mg to obtain minimal response. DISCUSSION: Sildenafil was shown to be helpful in the treatment of SSRI-induced sexual dysfunction. Three patients continued to experience ongoing positive effects after discontinuation of sildenafil; the other 10 patients relapsed.