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Aims To analyse the safety and impact on maintenance of sinus rhythm of transoesophageal echocardiographically guided early cardioversion associated with short-term anticoagulation in a large series of patients with atrial fibrillation and atrial flutter. Methods and Results Patients who were candidates for cardioversion were eligible for inclusion if they had atrial fibrillation or atrial flutter lasting longer than 2 days or of unknown duration. Patients received short-term anticoagulation with warfarin or heparin and underwent transthoracic echocardiography followed by transoesophageal echocardiography. Early cardioversion was performed if no thrombus was seen on the transoesophageal study. Warfarin was maintained for 1 month after cardioversion. In patients with atrial thrombi, cardioversion was deferred and prolonged anticoagulation was prescribed. The study population included 183 patients. One hundred and sixty nine patients without atrial thrombi underwent early cardioversion. Fourteen patients with atrial thrombi (7·6%) underwent a second transoesophageal echocardiogram after a median of 4 weeks of oral warfarin, and cardioversion was performed if clot regression was documented. No patient in our study population had a clinical thromboembolic event at 1 month follow-up (95% C.I. 0–0·016). The immediate success rate of cardioversion was better among patients with atrial fibrillation <4 weeks duration compared with patients with atrial fibrillation of longer or of unknown duration: 96·6% vs 85%, respectively (P=0·014). At 1 month follow-up, the percentage of arrhythmia relapses in patients with initially successful cardioversion was similar in the two groups (29% vs 26%, P=ns); thus the initial better outcome in patients with recent-onset arrhythmia was not lost. Conclusion Transoesophageal echocardiography-guided early cardioversion in concert with short-term anticoagulation is safe. This approach permits abbreviation of the overall duration of atrial fibrillation and has a better impact on the maintenance of sinus rhythm for patients in whom the duration of atrial fibrillation is <4 weeks. [ABSTRACT FROM PUBLISHER]

Tilt induced prolonged asystole has been considered to identify a distinct subgroup of patients with neurally mediated syncope and management including permanent pacemaker implantation has been suggested. To evaluate the reproducibility of asystolic response during head-up tilt testing (HUT), 33 patients with neurally mediated syncope and asystolic response (≥3 seconds) during HUT prospectively underwent two consecutive tests 13±15 days apart. On repeat tilt testing asystole was reproduced in 12 patients (36%), while 8 patients still had a positive HUT, but without asystole. Remarkably, 13 patients (40%) had a negative repeat HUT. Among 12 patients with asystole on both HUTs there was no significant difference in duration of asystole (14 371±11 430 ms vs 13 707±10 470 ms,P =ns) and time to syncope (36±20 min vs 37±20 min, P=ns) during initial and repeat HUTs. In conclusion, asystole during tilt testing does not seem to be a reproducible response. [ABSTRACT FROM PUBLISHER]

Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by "buffering" specific fatty acids., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pancreatitis is an inflammatory disease of the exocrine pancreas and ranks among the most common gastrointestinal disorders. Inflamed tissues frequently experience conditions of insufficient oxygen availability, or hypoxia. Here, we demonstrate that hypoxia and consequent stabilization of the hypoxia-inducible factor 1α (HIF1α) transcription factor occur in murine and human pancreatitis. Mice lacking pancreas-specific HIF1α expression display markedly impaired pancreatic regeneration following cerulein-induced pancreatitis, which is associated with excessive intrapancreatic B cell accumulation. Notably, B cell depletion in mice with established pancreatitis significantly enhances tissue regeneration. Our study reveals a crosstalk between pancreatic HIF1α expression and B cell trafficking that regulates tissue regeneration, and identifies plausible molecular targets for treating pancreatitis patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, with an exceedingly low 5-year survival rate. PDAC tumors are characterized by an extensive desmoplastic stromal response and hypovascularity, suggesting that tumor hypoxia could regulate PDAC initiation and/or progression. Using a well-defined, autochthonous Kras(G12D)-driven murine model, as well as human tumors, we demonstrate that hypoxia and stabilization of hypoxia-inducible factor 1α (HIF1α), a principal mediator of hypoxic adaptation, emerge early during preinvasive stages of PDAC. Surprisingly, pancreas-specific Hif1a deletion drastically accelerated Kras(G12D)-driven pancreatic neoplasia and was accompanied by significant increases in intrapancreatic B lymphocytes, featuring prominent influx of a rare "B1b" B-cell subtype. Finally, treatment of HIF1α-deficient mice with B cell-depleting αCD20 monoclonal antibodies inhibited progression of pancreatic intraepithelial neoplasia (PanIN). Our data reveal a previously unrecognized role for B cells in promoting pancreatic tumorigenesis and implicate HIF1α as a critical regulator of PDAC development., Significance: We show here that pancreas-specific Hif1a deletion promotes PDAC initiation, coincident with increased intrapancreatic accumulation of B cells, and that B-cell depletion suppresses pancreatic tumorigenesis. We therefore demonstrate a protective role for HIF1α in pancreatic cancer initiation and uncover a previously unrecognized function of B cells., (©2015 American Association for Cancer Research.)

Genetic studies suggest that the major events of human hair follicle development are similar to those in mice, but detailed analyses of this process are lacking. In mice, hair follicle placode "budding" is initiated by invagination of Wnt-induced epithelium into the underlying mesenchyme. Modification of adherens junctions (AJs) is clearly required for budding. Snail-mediated downregulation of AJ component E-cadherin is important for placode budding in mice. Beta-catenin, another AJ component, has been more difficult to study owing to its essential functions in Wnt signaling, a prerequisite for hair follicle placode induction. Here, we show that a subset of human invaginating hair placode cells expresses the stem cell marker CD133 during early morphogenesis. CD133 associates with membrane beta-catenin in early placodes, and its continued expression correlates with loss of beta-catenin and E-cadherin from the cell membrane at a time when E-cadherin transcriptional repressors Snail and Slug are not implicated. Stabilization of CD133 via anti-CD133 antibody treatment of human fetal scalp explants depresses beta-catenin and E-cadherin membrane localization. We discuss this unique correlation and suggest a hypothetical model whereby CD133 promotes morphogenesis in early hair follicle placodes through the localized removal of membrane beta-catenin proteins and subsequent AJ dissolution.

Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by γδ T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound-induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from γδ T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans.

Metacyclogenesis of Trypanosoma cruzi of the Y and Berenice strains was studied in Triatoma pseudomaculata and Rhodnius neglectus. Results in vivo showed a higher production of metacyclic trypomastigotes in R. neglectus' digestive tube than in T. pseudomaculata. In vitro experiments were also carried out in order to compare the behavior of culture forms of T. cruzi incubated in extracts of different compartments (stomach, intestine, and rectum) of the digestive tract of both species of triatomines. A higher percentage of metacyclic trypomastigotes for both parasite strains, Y and Berenice, was detected in the rectum extract of R. neglectus in comparison to that from T. pseudomaculata. The same results were obtained with in vitro experiments, using parasites incubated in urine from each of those vectors. The adhesion of parasites to the incubated rectum epithelial cells was also compared. In incubations with the Y strain no significant differences were detected between the two triatomine species but, however, with the Berenice strain the mean percentage of cells with adhered parasites was higher in R. neglectus than in T. pseudomaculata.

Tilt induced prolonged asystole has been considered to identify a distinct subgroup of patients with neurally mediated syncope and management including permanent pacemaker implantation has been suggested. To evaluate the reproducibility of asystolic response during head-up tilt testing (HUT), 33 patients with neurally mediated syncope and asystolic response (> or = 3 seconds) during HUT prospectively underwent two consecutive tests 13 +/- 15 days apart. On repeat tilt testing asystole was reproduced in 12 patients (36%), while 8 patients still had a positive HUT, but without asystole. Remarkably, 13 patients (40%) had a negative repeat HUT. Among 12 patients with asystole on both HUTs there was no significant difference in duration of asystole (14 371 +/- 11 430 ms vs 13 707 +/- 10 470 ms, P = ns) and time to syncope (36 +/- 20 min vs 37 +/- 20 min, P = ns) during initial and repeat HUTs. In conclusion, asystole during tilt testing does not seem to be a reproducible response.

Myocardial involvement is a common finding in patients with Duchenne-type muscular dystrophy (DMD). Nevertheless, the prognostic values of standard electrocardiogram (ECG), ventricular arrhythmias, ventricular late potentials (LPs), and left ventricular (LV) systolic dysfunction have not been extensively investigated. Eighty-four patients with DMD (aged 18.6 +/- 4.8 years) underwent standard and signal-averaged electrocardiography, 24-hour Holter monitoring, and echocardiography. The prevalence of electrocardiographic abnormalities, frequent ventricular premature complexes, LPs, and LV systolic dysfunction was 71%, 32%, 28%, and 35%, respectively. Median follow-up was 76 months (range 5 to 106). The mortality rate in the follow-up period was 27%. The typical DMD electrocardiographic alterations, ventricular arrhythmic pattern, and LPs were not predictors of mortality. In contrast, the presence of LV systolic dysfunction detected on echocardiography was a powerful predictor of mortality in the follow-up period (p = 0.013, hazard ratio 3.14, 95% confidence interval 1.27 to 7.79). Thus, echocardiographic assessment of LV systolic dysfunction provides prognostic information in patients with DMD. Electrocardiographic alterations, ventricular arrhythmias, and LPs have no prognostic value in predicting mortality in these patients.

Aims: To analyse the safety and impact on maintenance of sinus rhythm of transoesophageal echocardiographically guided early cardioversion associated with short-term anticoagulation in a large series of patients with atrial fibrillation and atrial flutter., Methods and Results: Patients who were candidates for cardioversion were eligible for inclusion if they had atrial fibrillation or atrial flutter lasting longer than 2 days or of unknown duration. Patients received short-term anticoagulation with warfarin or heparin and underwent transthoracic echocardiography followed by transoesophageal echocardiography. Early cardioversion was performed if no thrombus was seen on the transoesophageal study. Warfarin was maintained for 1 month after cardioversion. In patients with atrial thrombi, cardioversion was deferred and prolonged anticoagulation was prescribed. The study population included 183 patients. One hundred and sixty nine patients without atrial thrombi underwent early cardioversion. Fourteen patients with atrial thrombi (7.6%) underwent a second transoesophageal echocardiogram after a median of 4 weeks of oral warfarin, and cardioversion was performed if clot regression was documented. No patient in our study population had a clinical thromboembolic event at 1 month follow-up (95% C.I. 0-0.016). The immediate success rate of cardioversion was better among patients with atrial fibrillation < 4 weeks duration compared with patients with atrial fibrillation of longer or of unknown duration: 96.6% vs 85%, respectively (P = 0.014). At 1 month follow-up, the percentage of arrhythmia relapses in patients with initially successful cardioversion was similar in the two groups (29% vs 26%, P = ns); thus the initial better outcome in patients with recent-onset arrhythmia was not lost., Conclusion: Transoesophageal echocardiography-guided early cardioversion in concert with short-term anticoagulation is safe. This approach permits abbreviation of the overall duration of atrial fibrillation and has a better impact on the maintenance of sinus rhythm for patients in whom the duration of atrial fibrillation is < 4 weeks.

Few cases of atrial thrombosis detected by transesophageal echocardiography (TEE) in cardiac amyloidosis have been reported recently. We present the cases of 3 consecutive patients affected by AL-type cardiac amyloidosis, symptomatic for heart failure and in sinus rhythm. All patients had a cardiac restrictive pattern at Doppler examination. TEE showed left atrial thrombus in 2 patients and biatrial thrombi in 1 patient; conventional transthoracic echocardiography detected only 1 left atrial thrombus. Our experience confirms the association between cardiac amyloidosis and atrial thrombosis, even in sinus rhythm. TEE should be considered to assess thromboembolic risk in all cases of cardiac amyloidosis with severe diastolic dysfunction.

Background: Cardioversion of atrial fibrillation in nonanticoagulated patients may be associated with clinical thromboembolism. Prolonged anticoagulation with warfarin before cardioversion of atrial fibrillation produces a marked reduction of cardioversion-related thromboembolism. The benefit of anticoagulant therapy is generally believed to be due to atrial thrombi organization., Patients and Methods: Transesophageal echocardiography (TEE) is highly accurate for diagnosis of atrial thrombi and gives the possibility to serially evaluate the effects of anticoagulant therapy. One hundred twenty-three patients with atrial fibrillation lasting longer than 2 days underwent TEE before cardioversion. An atrial thrombus was identified in 11 patients (9%), and was always confined to the left atrial appendage. TEE was repeated after a median of 4 weeks of oral warfarin. Atrial thrombus had completely resolved in 9 of 11 patients (81.8%; 95% CI, 48.2 to 97.7%); in two patients, clot was still present. No patient had clinical thromboembolism between the two TEE studies., Conclusions: In the population of our study, a prolonged course of warfarin therapy was associated with resolution of atrial thrombi in the majority of patients. According to these data, the mechanism of thromboembolism reduction with 4 weeks of anticoagulation before cardioversion in patients with atrial fibrillation seems to be related mainly to thrombus lysis rather than organization. Due to the possibility of thrombus persistence even after prolonged anticoagulation, follow-up with TEE before cardioversion is necessary to document thrombus resolution.

The Fontan operation and its modifications can be relatively safely performed in the treatment of many complex congenital heart diseases, such as univentricular heart and tricuspid atresia. The main postoperative complications following the Fontan procedure and the incremental risk factors involved in their development are investigated. Between January 1984 and January 1988 eleven patients (6 females and 5 males), ranging in age from 2 to 15 years (mean age: 7.3 +/- 3.7) and in weight from 10.8 to 50 Kg (mean weight 22.3 +/- 12.7) underwent the Fontan operation in our Department. No hospital death occurred. The mean postoperative stay in the Intensive Care Unit was 6.3 +/- 3.9 days. There were two surgical re-entries for the same patient: cardiac tamponade (the day of operation) and residual atrial septal defect (2 days following the operation). Eight patients had significant signs of venous stasis, with severe hepatomegaly and pleural effusion. The 11 patients discharged were followed-up for a period of between 3 and 48 months (mean follow-up: 26.4 +/- 18). There were 2 cases of recurrent pleural effusion, 10 to 15 days after discharge. One late death occurred 2 years after the Fontan procedure (massive pulmonary embolism after re-operation). Short and medium-term rate of complications is related to increased post-operative values of mean right atrial pressure (greater than 15 mmHg). Mean right atrial pressures greater than 15 mmHg appear to be correlated with Nakata index values less than 250 mm2/m2. The experience reviewed confirms the excellent results of the Fontan operation, as regards survival and functional recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to evaluate the effects of short-term captopril administration on the response to cold pressor testing in normotensive and hypertensive subjects. Cold pressor testing was performed in 15 normotensive subjects and 15 hypertensive patients before and 90 minutes after captopril administration. Blood pressure and heart rate were measured before testing and at one-minute intervals from the beginning of cold pressor testing. Systolic time intervals were also assessed before and after testing. Captopril did not affect pressor responses to cold pressor testing in normotensive subjects or hypertensive patients. Basal heart rate (before testing) did not change, despite the decrease in blood pressure and showed a smaller increase in response to cold pressor testing in normotensive subjects, suggesting that captopril might interfere with arterial baroreflexes. The systolic time intervals were not modified by captopril except isometric contraction time; its basal value was reduced by captopril in both normotensive subjects and hypertensive patients. Cold exposure caused a similar increase in isometric contraction time before and after captopril in normotensive subjects, and the increase in isometric contraction time in hypertensive patients was greater. These findings suggest that captopril did not affect cardiac performance, indeed improving it, at least in basal conditions.