Isoproterenol Disrupts Intestinal Barriers Activating Gut-Liver-Axis: Effects on Intestinal Mucus and Vascular Barrier as Entry Sites.

BACKGROUND: The gut-liver-axis presents the pathophysiological hallmark for multiple liver diseases and has been proposed to be modulated during stress and shock. Access to the gut-liver-axis needs crossing of the mucus and gut-vascular barrier. The role of ß-adrenoreceptor-activation for both barriers has not been defined and is characterized here. METHODS: Splanchnic ß-adrenergic stimulation was achieved by chronic intraperitoneal application of isoproterenol via alzet-pump in vivo. The intestinal permeability and gut-vascular barrier function was assessed in ileal loop experiments. The extravasation of predefined sizes of fluorescence isothiocyanate (FITC)-dextran molecules in ileal microcirculation was evaluated by intravital confocal laser endomicroscopy in vivo. Mucus parameters thickness, goblet cell count and mucin-expression were assessed by stereomicroscopy, immunostaining and RNA-sequencing respectively. Ileal lamina propria (LP) as well as mesenteric lymph node mononuclear cells was assessed by FACS. RESULTS: Healthy mice lack translocation of 4 kDa-FITC-dextran from the small intestine to the liver, whereas isoproterenol-treated mice demonstrate pathological translocation (PBT). Mucus layer is reduced in thickness with loss of goblet-cells and mucin-2-staining and -expression in isoproterenol-treated animals under standardized gnotobiotic conditions. Isoproterenol disrupts the gut vascular barrier displaying Ileal extravasation of large-sized 70- and 150 kDa-FITC-dextran. This pathological endothelial permeability and accessibility induced by isoproterenol associates with an augmented expression of plasmalemmal-vesicle-associated-protein-1 in intestinal vessel. Ileal LP after isoproterenol treatment contains more CD11c+-dendritic cells (DC) with increased appearance of CCR7+ DC in mesenteric lymph nodes. CONCLUSIONS: Isoproterenol impairs the intestinal muco-epithelial and endothelial-vascular barrier promoting PBT to the liver. This barrier dysfunction on multiple levels potentially can contribute to liver injury induced by catecholamines during states of increased ß-adrenergic drive.

Dendritic cells produce TSLP that limits the differentiation of Th17 cells, fosters Treg development, and protects against colitis.

Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and keratinocytes, and is involved in immune homeostasis or inflammation. The mechanism through which TSLP regulates intestinal inflammation is unclear. Here, we report that mouse dendritic cells (DCs) express TSLP both in vitro and in vivo in response to Toll-like receptor ligation in a MyD88-dependent fashion. TSLP is produced by the CD103(+) subset of tolerogenic gut DCs and is downregulated during experimental colitis. TSLP produced by DCs acts directly on T cells by reducing their capacity to produce interleukin (IL)-17 and fostering the development of Foxp3(+) T cells. Consistently, TSLP protects against colitis development through a direct action on T cells, as adoptive transfer of naïve T cells from TSLPR(-/-) to SCID mice results in a more severe colitis, with increased frequency of IL-17-producing T cells and inflammatory cytokines. Hence, we describe a new anti-inflammatory role of TSLP in the gut.

Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells.

OBJECTIVE: In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (T(reg)) cells. Further, it was recently described that the cross-talk between human intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103+ tolerogenic DCs, and the function of primary CD103+ DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated. METHODS: Monocyte-derived DCs (MoDCs) and circulating CD1c+ DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn's disease and analysed for their ability to induce T(reg) cell differentiation. In some cases, transforming growth factor beta (TGFbeta), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103+ and CD103- DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in T(reg) cell differentiation experiments. RESULTS: It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ T(reg) cells. This control was lost in patients with Crohn's disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103+ DCs isolated from MLNs were endowed with the ability to drive T(reg) cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population. CONCLUSIONS: A population of tolerogenic CD103+ DCs was identified in the human gut that probably differentiate in response to IEC-derived factors and drive T(reg) cell development.

Dyspnoea and hypoxaemia after lung surgery: the role of interatrial right-to-left shunt.

After lung surgery, some patients complain of unexplained increased dyspnoea associated with hypoxaemia. This clinical presentation may be due to an interatrial right-to-left shunt despite normal right heart pressure. Some of these patients show postural dependency of hypoxaemia, whereas others do not. In this article, the pathogenesis and mechanisms involved in this post-surgical complication are discussed, and the techniques used for confirmation and localisation of shunt are reported. An invasive technique, such as right heart catheterisation with angiography, was often used in the past as the diagnostic procedure for the visualisation of interatrial shunt. As to noninvasive techniques, a perfusion lung scan may be used as the first approach as it may detect the effect of the right-to-left shunt by visualising an extrapulmonary distribution of the radioactive tracer. The 100% oxygen breathing test could also be used to quantify the amount of right-to-left shunt. Particular emphasis is given to newer imaging modalities, such as transoesophageal echocardiography, which is minimally invasive but highly sensitive in clearly visualising the atrial septum anatomy. Finally, the approach to closure of the foramen ovale or atrial septal defect is discussed. Open thoracotomy was the traditional approach in the past. Percutaneous closure has now become the most used and effective technique for the repair of the interatrial anatomical malformation.

Transcatheter closure of atrial septal defects with the STARFlex device: early results and follow-up.

BACKGROUND: The STARFlex (SF) device is a CardioSEAL (CS) double-umbrella device that has been modified by the addition of a self-centering mechanism comprised of nitinol springs connected between the two umbrellas and a flexible core wire with a pin-pivoting connection. This paper compares the results of atrial septal defect (ASD) closure with CardioSEAL and STARFlex devices. PATIENTS AND METHODS: Between December 1996 and March 2000, 117 patients underwent ASD closure with CardioSEAL (n = 79) and STARFlex (n = 38). The mean age (17 years), weight (49 kg), and ASD size (15 mm) were similar in the two groups. The procedures were performed under general anesthesia with both fluoroscopic and transesophageal echocardiographic monitoring. IMMEDIATE RESULTS: The devices were successfully implanted in all patients. Ten patients had multiple ASDs. A single device was used in four patients (CardioSEAL in three, STARFlex in one), while a simultaneous placement of two CardioSEAL (one patient) or two STARFlex (five patients) were performed in six patients. The results are summarized as follows: [table: see text] Follow-Up Results: On follow-up clinical exam, electrocardiograms, chest X-rays, and echocardiograms were obtained at 1, 6, and 12 months. [table: see text] During follow-up there were no deaths, endocarditis, rhythm disturbances, or other complications. Arm fractures were observed almost exclusively with large CardioSEAL devices (40 mm, less frequently with 33 mm), and only in one 33-mm STARFlex device. There were no clinical complications related to fractures. CONCLUSIONS: The STARFlex device seems to offer better results than the CardioSEAL, with significantly lower rates of residual shunts and arm fractures.

Repair of hemitruncus with autologous arterial ring and valved bioconduit.

We present a technical variant to reconstruct the right outflow tract in truncus type A3 (single pulmonary artery branch originating from the ascending aorta with common arterial valve and ventricular septal defect) with interposition of a ring of autologous arterial tissue and a bioconduit between the right ventricular infundibulum and the pulmonary artery branches. The final result is shown by postoperative angiogram which demonstrates an anatomically adequate reconstruction of the right ventricular outflow tract.

Long-term follow-up of stents implanted to relieve peripheral pulmonary arterial stenosis: hemodynamic findings and results of lung perfusion scanning.

In recent years, percutaneous placement of stents has been used as an alternative to surgery or balloon angioplasty for the treatment of adults with peripheral pulmonary arterial stenosis. This therapy has also been proposed for children, but questions still remain about its indications in this group of patients. We describe here the results of intravascular placement of stents in a group of 29 patients, with a mean age of 12+/-7 (range 3-31) years and weighing 35+/-19 (range 11-74) kg. All were affected by postsurgical or congenital isolated pulmonary arterial stenosis, and have now been followed for 38+/-19 (range 6-65) months. The early hemodynamic results have been excellent, with a significant reduction of the pulmonary arterial systolic pressure, the systolic pressure gradient, and the ratio of systolic pressures in the pulmonary and systemic circuits, and with a significant increase of the diameter of the stented vessels in all the patients. Of the 29 patients, 24 have been recatheterized 18+/-10 months after the procedure, demonstrating the stability of the results, with a low incidence of late restenosis, this seen in only 1 patient (2%). Lung perfusion scanning, performed in 17 patients each year after the follow-up catheterization, has showed that the results are maintained at long-term follow-up (51+/-9 months).

[Radiofrequency perforation in pulmonary valve atresia and intact ventricular septum]. / Perforazione con radiofrequenza della atresia valvolare polmonare a setto interventricolare intatto.

METHODS: Four neonates with Pulmonary Atresia and intact Ventricular Septum underwent Radiofrequency Valvotomy in our institution from October 1994 to June 1995. All patients had "membranous" atresia with confluent and normal size pulmonary branches; one of them had abnormal tricuspid tensor apparatus and severe right ventricular outflow tract hypertrophy. The right ventricle was considered of sufficient size to support biventricular circulation in all cases. In three patients the pulmonary arteries were supplied by the arterial duct maintained open with intravenous infusion of Prostaglandins. The other patient had previously undergone a modified left Blalock Taussig shunt in another institution. The cardiac catheterization was performed by the femoral venous and arterial routes, under general anesthesia. After delineating the atretic valve with angiography, a 5 French right Judkins catheter was placed in the right ventricular outflow tract just beneath the membrane. A 2 french radiofrequency catheter (Cerablate PA 120 Osypka) was then passed through the right Judkins; with a mean energy of 5-10 watts over 3-5 seconds the valve was perforated. After a predilation with a 2,5 mm balloon catheter (New Probe USCI or Cobra SCIMED), the valve was dilated with balloon catheters 20 to 30% larger than the anulus (Cristal Balloon BALT). RESULTS: In all cases the procedure was successful without any complication; a significant decrease of right ventricular pressure and an excellent antegrade flow across the valve were achieved. Two patients were weaned from prostaglandins by sixth and eighth day after the procedure. The patient with previous Bialock Taussig shunt showed a complete recovery of the right ventricle, but four months later underwent surgery for shunt closure and enlargement of the left pulmonary branch. These three patients are well at latest follow-up (5-10 months), with normal biventricular circulation. The other patient remained duct-dependent and was operated on of outflow patch and shunt nine days after the procedure, with good result; he unfortunately died the tenth postoperative day for complications of hemopericardium related to epicardial wires removal. CONCLUSIONS: In our opinion radiofrequency valvotomy is the first choice procedure in cases suitable for biventricular repair. In selected patients it may represent a definitive treatment.

Balloon aortic valvuloplasty in the first year of life.

Between February 1988 and September 1993 balloon aortic valvuloplasty was attempted in 33 consecutive patients in the first year of life: 20 patients (61%) were younger than 1 month. Major associated anomalies such as mitral stenosis, coarctation, and hypoplastic left ventricle were found in 11 cases (33%). The balloon dilation of the aortic valve was accomplished through the right carotid cut-down approach in neonates and patients with body weight < 5 kg, through a percutaneous femoral approach in the others; the procedure was completed in all. The peak systolic gradient across the aortic valve measured at catheterization fell from 80 +/- 33 mmHg (range 25-165) before the dilation to 27 +/- 17 mmHg (range 0-65), afterwards (p < 0.0001). The left ventricular ejection fraction increased from 44% +/- 26% to 61% +/- 17%, 24-48 hours after the procedure (p < 0.0001). Aortic insufficiency developed in 17 cases, being moderate in 2, mild in 6, and trivial in 9. Seven patients (21%), all in the first month of life, died within 30 days from the valvuloplasty; major associated anomalies were present in six; the death was due to a procedure related complication in one. No mortality was observed among the patients undergoing valvuloplasty beyond the first month of life. On follow-up (6 months to 6 years) aortic restenosis occurred in 3 cases; 1 was treated by surgical valvotomy, 2 by repeat balloon valvatomy; in another 2 cases, a subvalvular aortic obstruction developed and was relieved by surgical resection. There was no late mortality. Thus, balloon valvuloplasty appears to be an effective palliation for critical aortic stenosis in infancy. Early mortality is mainly related to associated anomalies.

[Pulmonary valvuloplasty]. / Valvuloplastica polmonare.

The aim of this study was to present the experience of 2 Institutions (Department of Cardiology in Bergamo and Department of Pediatric Cardiology, Apuano Pediatric Hospital in Massa) in performing the balloon dilatation of the pulmonary valve. From January 1985 to August 1993 the balloon pulmonary valvuloplasty was performed in 220 patients, age ranging from 1 day to 60 years (mean age 5 years), 55 (25%) in the first year of life, 17 (8%) in the first week of life. The systolic gradient across the pulmonary valve fell from 78 +/- 31 mmHg (range 40-160) to 20 +/- 16 mmHg (range 0-70) immediately after the procedure (p < 0.001). In-hospital mortality happened in 3 cases (1.3%); 2 of them were neonates with critical pulmonary stenosis. In 7 cases (3%) the balloon valvuloplasty was repeated afterwards, because of inadequate relief of the gradient after the first dilatation. During the mean follow-up period of 4 years the other 210 patients (95%) did not need any further treatment and remain in stable clinical conditions. The balloon valvuloplasty gives excellent early and intermediate term results and should be considered the first choice procedure in the treatment of pulmonary stenosis at all ages.

[The closure with a double-umbrella prosthesis of recanalized ducts after surgical ligation]. / Chiusura mediante protesi a doppio ombrellino di dotti ricanalizzati dopo legatura chirurgica.

Four patients of 5, 27, 27 and 62 years of age, who previously underwent surgical ligation of ductus arteriosus (respectively 3, 17, 19 and 17 years before), came to our observation because of recanalization of the duct. In three cases the duct was an isolated finding, whereas in the oldest patient the duct ligation had been accompanied by implantation of a Starr prosthesis in aortic position. The diagnosis of residual shunt was based on the auscultation of a continuous murmur at the left subclavicular space and on typical signs of patent ductus evidenced by Doppler interrogation. In all cases the diagnosis was confirmed by angiography; the minimal diameter of the ducts varied between 2.5 and 4 mm. Three umbrellas of 17 mm and one of 12 mm diameter were employed for the closure of the residual shunt. The implantation of the double-umbrella device was obtained with the routine transfemoral venous approach. In the youngest patient, in order to facilitate the progression of the transseptal catheter through the duct, it was necessary to create a circuit with the guide wire from the femoral vein to the contralateral femoral artery. In all four patients the shunt was completely abolished. The oldest patient underwent replacement of a malfunctioning aortic prosthesis three days after implantation of the double-umbrella device; the surgical approach was this way significantly simplified. The implantation of a Rashkind double-umbrella device is the method of choice for closure of residual shunts through the duct after surgical ligation.

[Left atrial thrombosis and acquired coronary artery fistulae: report of a case]. / Trombosi atriale sinistra e fistole coronariche acquisite. Descrizione di un caso.

Many cases of fistulae between coronary arteries and heart chambers are now detectable because of improvement in selective coronary artery angiography. Coronary fistulae may be congenital or secondary to cardiac disease such as atrial tumors, mitral stenosis with atrial thrombosis or ventricular aneurysm. A case of a patient with rheumatic heart disease and multiple fistulae between coronary arteries and left atrium, is reported. A thin mural thrombus adherent to the left atrial wall, unsuspected preoperatively, was discovered at surgery and gave the clue to the pathological origin of the fistulae.