Pasquale Ferraro

Results of the Collis-Nissen gastroplasty in patients with Barrett's esophagus.

BACKGROUND Barretts esophagus (BE) is an advanced stage of gastroesophageal reflux disease. Medical treatment and standard antireflux operations show a high failure rate. An elongated gastroplasty, wrapped by a total fundoplication should provide a tension-free repair with adequate protection against reflux. The aim of this study is to review the operative effects of a Collis-Nissen gastroplasty to treat reflux in Barretts esophagus. METHODS From January 1989 to December 1997, 45 patients with BE (38 men, 7 women) aged 53.5 years, underwent a Collis-Nissen gastroplasty. Mean follow-up is 35.9 months (range, 6 to 110 months). Pre- and postoperative evaluations included symptom assessment, esophagogram, endoscopy, manometry, 24-hour pH study, and esophageal emptying scintigrams. RESULTS There were no operative deaths. All reflux symptoms were controlled. Acid reflux was significantly reduced (percent time exposure decreased from 10% to 1%) and lower esophageal sphincter (LES) pressure were restored to normal (LES gradient increased from 4 mm Hg to 11 mm Hg). LES incomplete relaxation was noted in 50% of patients postoperatively. Endoscopically, mucosal damage from reflux healed but the columnar mucosa with intestinal metaplasia persisted. CONCLUSIONS The Collis-Nissen gastroplasty, in patients with BE, controls reflux disease, its symptoms, and the mucosal damage associated with this condition. It restores the LES gradient but increases the resistance to bolus transit. There is no regression of the abnormal mucosa despite reflux control.

Preoperative embolization in the management of a mediastinal paraganglioma

Parangliomas are rare and highly vascular tumors of neuroendocrine cell origin which are treated by complete surgical resection. Preoperative embolization to reduce perioperative bleeding complications, although described in paragangliomas of the neck and carotid body, has never before been described in the case of a mediastinal paraganglioma. The following is a presentation of such a case of mediastinal paraganglioma, in which embolization was used successfully before surgical resection.

Improvement of defective cystic fibrosis airway epithelial wound repair after CFTR rescue

Airway damage and remodelling are important components of lung pathology progression in cystic fibrosis (CF). Although repair mechanisms are engaged to restore the epithelial integrity, these processes are obviously insufficient to maintain lung function in CF airways. Our aims were therefore to study how the basic cystic fibrosis transmembrane conductance regulator (CFTR) defect could impact epithelial wound healing and to determine if CFTR correction could improve it. Wound-healing experiments, as well as cell migration and proliferation assays, were performed to study the early phases of epithelial repair in human CF and non-CF airway cells. CFTR function was evaluated using CFTR small interferring (si)RNA and inhibitor GlyH101 in non-CF cells, and conversely after CFTR rescue with the CFTR corrector VRT-325 in CF cells. Wound-healing experiments first showed that airway cells from CF patients repaired slower than non-CF cells. CFTR inhibition or silencing in non-CF primary airway cells significantly inhibited wound closure. GlyH101 also decreased cell migration and proliferation. Interestingly, wild-type CFTR transduction in CF airway cell lines or CFTR correction with VRT-325 in CFBE-&Dgr;F508 and primary CF bronchial monolayers significantly improved wound healing. Altogether our results demonstrated that functional CFTR plays a critical role in wound repair, and CFTR correction may represent a novel strategy to promote the airway repair processes in CF.

Role of the cystic fibrosis transmembrane conductance channel in human airway smooth muscle.

Patients with cystic fibrosis (CF) suffer from asthma-like symptoms and gastrointestinal cramps, attributed to a mutation in the CF transmembrane conductance regulator (CFTR) gene present in a variety of cells. Pulmonary manifestations of the disease include the production of thickened mucus and symptoms of asthma, such as cough and wheezing. A possible alteration in airway smooth muscle (ASM) cell function of patients with CF has not been investigated. The aim of this study was to determine whether the (CFTR) channel is present and affects function of human ASM cells. Cell cultures were obtained from the main or lobar bronchi of patients with and without CF, and the presence of the CFTR channel detected by immunofluorescence. Cytosolic Ca(2+) was measured using Fura-2 and dual-wavelength microfluorimetry. The results show that CFTR is expressed in airway bronchial tissue and in cultured ASM cells. Peak Ca(2+) release in response to histamine was significantly decreased in CF cells compared with non-CF ASM cells (357 +/- 53 nM versus 558 +/- 20 nM; P < 0.001). The CFTR pharmacological blockers, glibenclamide and N-phenyl anthranilic acid, significantly reduced histamine-induced Ca(2+) release in non-CF cells, and similar results were obtained when CFTR expression was varied using antisense oligonucleotides. In conclusion, these data show that the CFTR channel is present in ASM cells, and that it modulates the release of Ca(2+) in response to contractile agents. In patients with CF, a dysfunctional CFTR channel could contribute to the asthma diathesis and gastrointestinal problems experienced by these patients.

Gabapentin does not reduce post-thoracotomy shoulder pain: a randomized, double-blind placebo-controlled study.

Purpose: Despite adequate epidural analgesia, up to 97% of patients undergoing thoracotomy experience ipsilateral shoulder pain. In this setting, this study evaluated the safety and the efficacy of pre-emptive gabapentin.Methods: A double-blind, placebo-controlled study was undertaken in 51 patients randomized into two groups. Two hours before surgery, 23 patients received gabapentin 1200 mgpo (Group G), and 28 patients received placebo (Group P). Shoulder pain and postoperative pain, at the surgical site, were monitored every four hours for 24 hr, using a numerical rating scale. Subcutaneous hydromorphone was administered for rescue analgesia against shoulder pain.Results: Forty-four patients complained of shoulder pain (prevalence of 86%). Demographic and surgical data were similar between the two groups. There were no significant differences in the total cumulative doses of hydromorphone administered at eight, 16, and 24 hr, nor were there differences in individual numerical rating scale scores for shoulder pain. The groups were similar with respect to the degree of pain at the surgical site. The frequency of side effects between groups at corresponding time intervals was also similar, with the exception of sedation. At four hours, the incidence of sedation scores τ; 1 was greater in Group G (21/23 patients), compared to Group P (18/28 patients;P=0.025). In contrast, by 24 hr, 5/18 patients in Group P had sedation scores τ;1, compared to 0/28 patients in Group G (P=0.05).Conclusion: Pre-emptively administered gabapentin, 1200 mg, does not reduce the incidence, or the severity, of post-thoracotomy shoulder pain in patients receiving thoracic epidural analgesia.RésuméObjectif: Malgré une analgésie péridurale adaptée, jusqu’à 97. % des patients subissant une thoracotomie éprouvent de la douleur à l’épaule ipsilatérale. Dans ce contexte, notre étude a évalué l’innocuité et l’efficacité de la gabapentine administrée de façon préventive.Méthode: Une étude à double insu et contrôlée par placebo a été menée ; elle évaluait 51 patients randomisés en deux groupes. Deux heures avant la chirurgie, 23 patients ont reçu de la gabapentine 1200 mg oralement (groupe G) et 28 un placebo (groupe P). La douleur à l’épaule et la douleur postopératoire au site chirurgical ont été évaluées toutes les quatre heures durant 24 h à l’aide d’une échelle d’évaluation numérique. De l’hydromorphone souscutanée a été administrée en analgésie de secours contre la douleur à l’épaule.Résultats: Quarante-quatre patients se sont plaints de douleur à l’épaule (prévalence de 86 %). Les données démographiques et chirurgicales étaient semblables dans les deux groupes. Il n’y a pas eu de différence significative dans les doses cumulatives totales d’hydromorphone administrée à huit, seize et 24 h, ni dans les scores individuels sur l’échelle d’évaluation numérique pour la douleur à l’épaule. Les groupes ont présenté des résultats semblables concernant le degré de douleur au site chirurgical. La fréquence des effets secondaires, comparée entre les groupes à des intervalles correspondants, était également similaire, à l’exception de la sédation. À quatre heures, l’incidence de scores de sédation τ;1 était plus élevée dans le groupe G (21/23 patients), comparé au groupe P (18/28 patients; P=0,025). En revanche, à 24 heures, 5/18 patients du groupe P présentaient des scores de sédation τ;1, comparé à 0/28 patients dans le groupe G (P=0,05).Conclusion: La gabapentine 1200 mg administrée de façon préventive ne réduit pas l’incidence ou la sévérité de la douleur à l’épaule post-thoracotomie chez les patients recevant une analgésie péridurale thoracique.

End-stage achalasia

Despite symptom improvement offered to achalasia patients by either pneumatic dilation or surgical myotomy, 10% to 15% of those so treated will present progressive deterioration of their esophageal function and up to 5% may eventually require an esophagectomy. The natural evolution of achalasia to its end stage as well as the timing of esophagectomy in these patients form the basis of this review. The optimal reconstruction for the decompensated resected esophagus will also be explored: gastric interposition, colon interposition, and jejunal interposition all have their respective advantages and disadvantages. Their use is examined in the exclusive context of resection for achalasia.

Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype

IL-13 is an important mediator of allergen-induced airway hyperresponsiveness. This Th2 cytokine, produced by activated T cells, mast cells, and basophils, has been described to mediate a part of its effects independently of inflammation through a direct modulation of the airway smooth muscle (ASM). Previous studies demonstrated that IL-13 induces hyperresponsiveness in vivo and enhances calcium signaling in response to contractile agonists in vitro. We hypothesized that IL-13 drives human ASM cells (ASMC) to a procontractile phenotype. We evaluated ASM phenotype through the ability of the cell to proliferate, to contract, and to express contractile protein in response to IL-13. We found that IL-13 inhibits human ASMC proliferation (expression of Ki67 and bromodeoxyuridine incorporation) in response to serum, increasing the number of cells in G0/G1 phase and decreasing the number of cells in G2/M phases of the cell cycle. IL-13-induced inhibition of proliferation was not dependent on signal transducer and activator of transcription-6 but was IL-13Rα2 receptor dependent and associated with a decrease of Kruppel-like factor 5 expression. In parallel, IL-13 increased calcium signaling and the stiffening of human ASMC in response to 1 μM histamine, whereas the stiffening response to 30 mM KCl was unchanged. However, Western blot analysis showed unchanged levels of calponin, smooth muscle α-actin, vinculin, and myosin. We conclude that IL-13 inhibits proliferation via the IL-13Rα2 receptor and induces hypercontractility of human ASMC without change of the phenotypic markers of contractility.

Mucosal damage in the esophageal remnant after esophagectomy and gastric transposition.

Objective:To assess development of mucosal damage in the esophageal remnant in regard to the level of the esophagogastrostomy reconstruction either in a right chest or in a left neck position. Summary Background Data:Esophagectomy with gastric interposition creates an in vivo human model of pathologic esophageal reflux with the potential for long-term reflux disease complications. Methods:Eighty-four esophagectomy patients were assessed over time by symptoms, endoscopy and biopsies of their esophageal remnant after the operation. The anastomosis was in the right upper chest (n = 36) or in a left cervical position (n = 48). Visual quantification of damage, details of histopathology, and time period since surgery were recorded. Results:Twenty-nine patients (81%) with a right chest reconstruction had reflux symptoms when compared with 25 patients (53%) with a neck reconstruction (P = 0.007). Visualized reflux esophagitis was observed in 31 patients (81%) with chest anastomoses and in 22 patients (46%) with cervical anastomoses (P = 0.006). Documented mucosal damage and columnar lined metaplasia were significantly more frequent in the chest anastomosis group than the cervical group. The median of all mucosal damage and columnar lined metaplastic-free evolution were 13 ± 3 and 20.5 ± 6 months for the intrathoracic anastomosis, and 22 ± 6 months and 40 ± 8 months for the cervical anastomosis (P = 0.087). Two factors affecting the development of metaplasia were included in the multivariate analysis: an intrathoracic anastomosis (P = 0.018) and the presence of a previous Barrett esophagus (P = 0.064). Conclusions:When a gastric transplant is used after esophagectomy, a high prevalence of mucosal damage is observed in the esophageal remnant independently of the level of reconstruction. A left cervical anastomosis favors less reflux symptoms, less visualized damage, and delays the development of mucosal damage over time.

Enhanced Ca2+ entry due to Orai1 plasma membrane insertion increases IL-8 secretion by cystic fibrosis airways

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, causes retention of CFTR in the endoplasmic reticulum (ER). Some CF abnormalities can be explained by altered Ca2+ homeostasis, although it remains unknown how CFTR influences calcium signaling. This study examined the novel hypothesis that store‐operated calcium entry (SOCE) through Orai1 is abnormal in CF. The significance of Orai1‐mediated SOCE for increased interleukin‐8 (IL‐8) expression in CF was also investigated. CF and non‐CF human airway epithelial cell line and primary cells (obtained at lung transplantation) were used in Ca2+ imaging, electrophysiology, and fluorescence imaging experiments to explore differences in Orai1 function in CF vs. non‐CF cells. Protein expression and localization was assessed by Western blots, cell surface biotinylation, ELISA, and image correlation spectroscopy (ICS). We show here that store‐operated Ca2+ entry (SOCE) is elevated in CF human airway epithelial cells (hAECs; ~1.8‐ and ~2.5‐fold for total Ca2+i increase and Ca2+ influx rate, respectively, and ~2‐fold increase in the ICRAC current) and is caused by increased exocytotic insertion (~2‐fold) of Orai1 channels into the plasma membrane, which is normalized by rescue of ΔF508‐CFTR trafficking to the cell surface. Augmented SOCE in CF cells is a major factor leading to increased IL‐8 secretion (~2‐fold). CFTR normally down‐regulates the Orai1/stromal interaction molecule 1 (STIM1) complex, and loss of this inhibition due to the absence of CFTR at the plasma membrane helps to explain the potentiated inflammatory response in CF cells.—Balghi, H., Robert, R., Rappaz, B., Zhang, X., Wohlhuter‐Haddad, A., Evagelidis, A., Luo, Y., Goepp, J., Ferraro, P., Roméo, P., Trebak, M., Wiseman, P. W., Thomas, D. Y., Hanrahan, J. W. Enhanced Ca2+ entry due to Orai1 plasma membrane insertion increases IL‐8 secretion by cystic fibrosis airways. FASEB J. 25, 4274–4291 (2011). www.fasebj.org

MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells

Interleukin-13 (IL-13) has been strongly implicated in the pathogenesis of allergic asthma through animal models that have shown that IL-13 is both necessary and sufficient to cause airway hyperresponsiveness (AHR). Airway smooth muscle (ASM) is a primary effector of AHR, and IL-13 increases the responsiveness of ASM, by increasing Ca(2+) release intracellularly, to bronchoconstrictors such as histamine. The mechanisms and signaling pathways mediating this effect are incompletely understood. We have investigated the pathways through which IL-13 regulates the Ca(2+) response to histamine in primary human ASM cell cultures. Functional IL-13 receptors were demonstrated by IL-13-mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and mitogen-activated protein kinases (MAPKs). IL-13 increased Ca(2+) responses to histamine. The augmentation of Ca(2+) signaling was not affected by inhibition of STAT6 or p38 MAPK signaling but was prevented by concurrent inhibition of c-jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) MAPKs. This inhibition did not affect the IL-13-induced increase in histamine receptors. We conclude that IL-13 induces potentiation of Ca(2+) responses to contractile agonists by affecting mechanisms downstream of receptors. JNK and ERK MAPKs modulate these mechanisms.