Impact of species hybridization on the clinical management of schistosomiasis: A prospective study.

BACKGROUND: Species hybridization represents a real concern in terms of parasite transmission, epidemiology and morbidity of schistosomiasis. It is greatly important to better understand the impact of species hybridization for the clinical management. METHODS: A prospective observational study was carried out in sub-Saharan migrants who were diagnosed with confirmed genitourinary schistosomiasis. A tailored protocol was applied, including Schistosoma serology, a specific urine LAMP tests for schistosomiasis and an ultrasound examination before treatment with praziquantel. A scheduled follow-up was performed at 3, 6 and 12 months to monitor treatment response, comparing patients carriers of Schistosoma hybrids with carriers of only genetically pure forms. RESULTS: A total of 31 male patients from West Africa were included in the study with a mean age of 26.5 years. Twelve (38.7 %) of the patients were carriers of Schistosoma hybrids. As compared with patients infected with S. haematobium alone, hybrid carriers had lower haemoglobin levels (13.8 g/dL [SD 1.8] vs 14.8 g/dL [SD 1.4], p = 0.04), a greater frequency of hematuria (100 % vs 52.6 %, p = 0.005), a higher ultrasound score (2.64, SD 2.20 vs 0.89, SD 0.99; p = 0.02). However, the presence of hybrids did not result in differences in clinical and analytical responses after treatment. CONCLUSIONS: The presence of Schistosoma hybrids seems to cause increased morbidity in infected individuals. However, it does not appear to result in differences in diagnostic tests or in clinical and analytical responses after treatment.

Evaluation of Current Methods to Detect Cellular Leucine-Rich Repeat Kinase 2 (LRRK2) Kinase Activity.

BACKGROUND: Coding variation in the Leucine rich repeat kinase 2 gene linked to Parkinson's disease (PD) promotes enhanced activity of the encoded LRRK2 kinase, particularly with respect to autophosphorylation at S1292 and/or phosphorylation of the heterologous substrate RAB10. OBJECTIVE: To determine the inter-laboratory reliability of measurements of cellular LRRK2 kinase activity in the context of wildtype or mutant LRRK2 expression using published protocols. METHODS: Benchmark western blot assessments of phospho-LRRK2 and phospho-RAB10 were performed in parallel with in situ immunological approaches in HEK293T, mouse embryonic fibroblasts, and lymphoblastoid cell lines. Rat brain tissue, with or without adenovirus-mediated LRRK2 expression, and human brain tissues from subjects with or without PD, were also evaluated for LRRK2 kinase activity markers. RESULTS: Western blots were able to detect extracted LRRK2 activity in cells and tissue with pS1292-LRRK2 or pT73-RAB10 antibodies. However, while LRRK2 kinase signal could be detected at the cellular level with over-expressed mutant LRRK2 in cell lines, we were unable to demonstrate specific detection of endogenous cellular LRRK2 activity in cell culture models or tissues that we evaluated. CONCLUSION: Further development of reliable methods that can be deployed in multiple laboratories to measure endogenous LRRK2 activities are likely required, especially at cellular resolution.

Long-term recurrences and mortality in patients with noncardiac syncope.

INTRODUCTION AND OBJECTIVES: There are no in-depth studies of the long-term outcome of patients with syncope after exclusion of cardiac etiology. We therefore analyzed the long-term outcome of this population. METHODS: For 147 months, we included all patients with syncope referred to our syncope unit after exclusion of a cardiac cause. RESULTS: We included 589 consecutive patients. There were 313 (53.1%) women, and the median age was 52 [34-66] years. Of these, 405 (68.8%) were diagnosed with vasovagal syncope (VVS), 65 (11%) with orthostatic hypotension syncope (OHS), and 119 (20.2%) with syncope of unknown etiology (SUE). During a median follow-up of 52 [28-89] months, 220 (37.4%) had recurrences (21.7% ≥ 2 recurrences), and 39 died (6.6%). Syncope recurred in 41% of patients with VVS, 35.4% with OHS, and 25.2% with SUE (P=.006). In the Cox multivariate analysis, recurrence was correlated with age (P=.002), female sex (P <.0001), and the number of previous episodes (< 5 vs ≥ 5; P <.0001). Death occurred in 15 (3.5%) patients with VVS, 11 (16.9%) with OHS, and 13 (10.9%) with SUE (P=.001). In the multivariate analysis, death was associated with age (P=.0001), diabetes (P=.007), and diagnosis of OHS (P=.026) and SUE (P=.020). CONCLUSIONS: In patients with noncardiac syncope, the recurrence rate after 52 months of follow-up was 37.4% and mortality was 6.6% per year. Recurrence was higher in patients with a neuromedial profile and mortality was higher in patients with a nonneuromedial profile.

Usefulness of ultrasound in sub-Saharan patients with a serological diagnosis of schistosomiasis.

OBJECTIVE: To evaluate the usefulness of ultrasound examination in patients with just a serological diagnosis of schistosomiasis but no other evidence of active infection. METHODS: 346 sub-Saharan patients with possible schistosomiasis that presented at a Tropical Medicine Unit between 2008 and 2019 were retrospectively selected. Possible schistosomiasis was considered in those patients with a positive serology for schistosomasis in the absence of direct microbiological isolates, hematuria and/or eosinophilia. Data from ultrasound examinations before and after treatment with praziquantel were collected and categorized following the World Health Organization-Niamey score to standardize the use of ultrasonography for the assessment of schistosomiasis-related morbidity. RESULTS: Ultrasound examinations were abnormal in only ten patients (2.89%). Main findings were focal thickening of the bladder wall (n = 6), ureteral dilatation (n = 3) and grade I hydronephrosis (n = 1). No malignant lesions, hepatic lesions nor hepatobiliary related disorders were found. After treatment, the S. haematobium global score (5 vs 3.4, p = 0.06) and the urinary bladder score (2 vs 1, p = 0.059) showed a trend towards improvement after treatment. In three patients the score after treatment dropped to 0, and in another three it remained the same although with signs of improvement. No worsening of the score was observed in any case. CONCLUSION: For those patients with a diagnosis of schistosomiasis based solely in a positive serology, the ultrasound examination could safely be spared due to the low prevalence of pathological findings and its response to treatment anyway.

Clinical impact of rotational thromboelastometry in cardiac surgery.

Patients undergoing cardiac surgery are at high risk of postoperative bleeding, which is related to worse prognosis and survival. The use of ROTEM®, together with the implementation of a specific treatment algorithm, to reduce the risk of postoperative bleeding. An observational, comparative, cross-case study with historical controls. A total of 1772 consecutive patients admitted to intensive care unit after having undergone cardiac surgery, was divided into 3 groups: Group 1: Coagulation was only monitored by the classical coagulation test (control group). Group 2: Monitorization was done by ROTEM®, according to a protocol designed in our center. Group 3: VerifyNow® was added to ROTEM®, implementing a specific treatment algorithm. We observed a decreased of red blood cell transfusion (Group 1 55.5%, Group 2 52.7%, Group 3 46.6%, P<0.01). Postoperative results include a significant reduction in complications with a marked improvement in overall survival in the ROTEM® - guided groups. Conclusions: Monitoring of hemostasis by POCT'S (ROTEM® and VerifyNow®) in patients undergoing cardiac surgery and cardiac transplantation was associated with a decreased incidence of blood transfusion, postoperative clinical complications, and mortality.

TRPC Channels: Dysregulation and Ca2+ Mishandling in Ischemic Heart Disease.

Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP channels, TRPC channels may form homo or heterotetrameric ion channels, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase in the expression of different TRPC isoforms was observed in different animal models of heart infarcts and in vitro experimental models of ischemia and reperfusion. TRPC channel-mediated increase of the intracellular Ca2+ concentration seems to be required for the activation of the signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angiogenesis. In this review, we highlight the current knowledge regarding TRPC implication in different cellular processes related to ischemia and reperfusion and to heart infarction.

Severe complications of imported schistosomiasis, Spain: A retrospective observational study.

BACKGROUND: Chronic schistosomiasis silently leads to severe organ-specific disorders, such as hydroureter, bladder cancer or portal hypertension in around 10% of infected people in endemic zones. However, in non-endemic areas, information on schistosomiasis' severe complications and their actual prevalence is scarce because diagnosis is usually reached when such complications are well established. METHODS: Retrospective observational study of data obtained from a screening protocol designed for sub-Saharan migrants including search for stool parasites and schistosoma serology. After screening 3090 sub-Saharans, 326 (10.5%) confirmed cases of schistosomiasis were found, based on detection of ova in feces, urine or in biopsy samples. Another 830 patients (26.9%) were diagnosed of probable schistosomiasis (positive serology and/or suggestive imaging findings). RESULTS: Only patients with confirmed schistosomiasis were included in the final analysis. Among them, 13 (4%) presented severe complications at the time of diagnosis. Depending on the location, they account for 5% of patients with hepatointestinal schistosomiasis and 3.5% of patients with urogenital infection. CONCLUSIONS: Targeted systematic screening could reduce the prevalence of severe complications by enabling early diagnosis and treatment. Having indigenous transmission been demonstrated in southern Europe, prevention of future cases in non-endemic countries might be another sound reason supporting such screening.

Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients.

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cell-derived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients.

Apical Muscular Ventricular Septal Defects: Surgical Strategy Using Three-Dimensional Printed Model.

To evaluate the utility of a three-dimensional printed model (3D-model) for surgical decision planning in a complex case of multiple ventricular septal defect (VSD) (so-called Swiss-cheese septum). A 3 month-old-girl with diagnosis of multiple apical VSDs in the trabecular septum, perimembranous VSD, and atrial septal defect that resulted in congestive heart failure was referred for surgical intervention. Due to inconclusive understanding of the total number, openings and locations of the apical VSDs, there were concerns regarding the best surgical approach. Using computed tomography images, a 3D-model was fabricated by fused deposition modeling of polyurethane filament. The 3D model helped identifying the total number of VSD, their origins and exits as well as the minimum number of septal bands to resect, the optimal patch size and morphology to completely close all VSDs without reducing significantly the RV cavity. The procedure was successfully replicated in the patient by right atrial approach, resulting in good RV cavity size, function and no residual VSDs evaluated by transesophageal echocardiography. Direct evaluation of the 3D printed replica anatomy and surgical simulation may help optimizing surgical approach, patch size and location and therefore it might reduce complications and residual defects.

Urocortin-2 Prevents Dysregulation of Ca2+ Homeostasis and Improves Early Cardiac Remodeling After Ischemia and Reperfusion.

Aims: Urocortin-2 (Ucn-2) is a potent cardioprotector against Ischemia and Reperfusion (I/R) injuries. However, little is known about its role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) under I/R. Here, we examined whether the addition of Ucn-2 in reperfusion promotes cardioprotection focusing on ([Ca2+]i handling. Methods and Results: Cardiac Wistar rat model of I/R was induced by transient ligation of the left coronary artery and experiments were conducted 1 week after surgery in tissue and adult cardiomyocytes isolated from risk and remote zones. We observed that I/R promoted significant alteration in cardiac contractility as well as an increase in hypertrophy and fibrosis in both zones. The study of confocal [Ca2+]i imaging in adult cardiomyocytes revealed that I/R decreased the amplitude of [Ca2+]i transient and cardiomyocytes contraction in risk and remote zones. Interestingly, intravenous infusion of Ucn-2 before heart's reperfusion recovered significantly cardiac contractility and prevented fibrosis, but it didn't affect cardiac hypertrophy. Moreover, Ucn-2 recovered the amplitude of [Ca2+]i transient and modulated the expression of several proteins related to [Ca2+]i homeostasis, such as TRPC5 and Orai1 channels. Using Neonatal Rat Ventricular Myocytes (NRVM) we demonstrated that Ucn-2 blunted I/R-induced Store Operated Ca2+ Entry (SOCE), decreased the expression of TRPC5 and Orai1 as well as their interaction in reperfusion. Conclusion: Our study provides the first evidences demonstrating that Ucn-2 addition at the onset of reperfusion attenuates I/R-induced adverse cardiac remodeling, involving the [Ca2+]i handling and inhibiting the expression and interaction between TRPC5 and Orai1.

Quality of life, satisfaction and outcomes after ministernotomy versus full sternotomy isolated aortic valve replacement (QUALITY-AVR): study protocol for a randomised controlled trial.

BACKGROUND: During the last decade, the use of ministernotomy in cardiac surgery has increased. Quality of life and patient satisfaction after ministernotomy have never been compared to conventional full sternotomy in randomised trials. The aim of the study is to determine if this minimally invasive approach improves quality of life, satisfaction and clinical morbimortality outcomes. METHODS/DESIGN: The QUALITY-AVR trial is a single-blind, single-centre, independent, and pragmatic randomised clinical trial comparing ministernotomy ("J" shaped upper hemisternotomy toward right 4th intercostal space) to full sternotomy in patients with isolated severe aortic stenosis scheduled for elective aortic valve replacement. One hundred patients will be randomised in a 1:1 computational fashion. Sample size was determined for the primary end point with alpha error of 0.05 and with power of 90% in detecting differences between intervention groups of ≥ 0.10 points in change from baseline quality of life Questionnaire EuroQOL-index (EQ-5D-5 L®), measured at 1, 6 or 12 months. Secondary endpoints are: the differences in change from other baseline EQ-5D-5 L® utilities (visual analogue scale, Health Index and Severity Index), cardiac surgery specific satisfaction questionnaire (SATISCORE®), a combined safety endpoint of four major adverse complications at 1 month (all-cause mortality, acute myocardial infarction, neurologic events and acute renal failure), bleeding through drains within the first 24 h, intubation time, postoperative hospital and intensive care unit length of stay, transfusion needs during the first 72 h and 1-year survival rates. Clinical follow up is scheduled at baseline, 1, 6, and 12 months after randomization. All clinical outcomes are recorded following the Valve Academic Research Consortium 2 criteria. DISCUSSION: The QUALITY-AVR trial aims to test the hypothesis that ministernotomy improves quality of life, satisfaction and clinical outcomes in patients referred for isolated aortic valve replacement. Statistically significant differences favouring ministernotomy could modify the surgical "gold standard" for aortic stenosis surgery, and subsequently the need to change the control group in transcatheter aortic valve implantation trials. Recruitment started on 18 March 2016. In November 2017, 75 patients were enrolled. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02726087 . Registered on 13 March 2016.

Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation.

BACKGROUND: Mutations in LRRK2 are a common genetic cause of Parkinson's disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive. METHODS: Human neuroblastoma SH-SY5Y cells stably expressing wildtype or pathogenic LRRK2 were used to test for polarity defects in the context of centrosomal positioning. Centrosomal cohesion deficits were analyzed from transiently transfected HEK293T cells, as well as from two distinct peripheral cell types derived from LRRK2-PD patients. Kinase assays, coimmunoprecipitation and GTP binding/retention assays were used to address Rab8a phosphorylation by LRRK2 and its effects in vitro. Transient transfections and siRNA experiments were performed to probe for the implication of Rab8a and its phosphorylated form in the centrosomal deficits caused by pathogenic LRRK2. RESULTS: Here, we show that pathogenic LRRK2 causes deficits in centrosomal positioning with effects on neurite outgrowth, cell polarization and directed migration. Pathogenic LRRK2 also causes deficits in centrosome cohesion which can be detected in peripheral cells derived from LRRK2-PD patients as compared to healthy controls, and which are reversed upon LRRK2 kinase inhibition. The centrosomal cohesion and polarity deficits can be mimicked when co-expressing wildtype LRRK2 with wildtype but not phospho-deficient Rab8a. The centrosomal defects induced by pathogenic LRRK2 are associated with a kinase activity-dependent increase in the centrosomal localization of phosphorylated Rab8a, and are prominently reduced upon RNAi of Rab8a. CONCLUSIONS: Our findings reveal a new function of LRRK2 mediated by Rab8a phosphorylation and related to various centrosomal defects.

Three-dimensional printed models for surgical planning of complex congenital heart defects: an international multicentre study.

OBJECTIVES: To evaluate the impact of 3D printed models (3D models) on surgical planning in complex congenital heart disease (CHD). METHODS: A prospective case-crossover study involving 10 international centres and 40 patients with complex CHD (median age 3 years, range 1 month-34 years) was conducted. Magnetic resonance imaging and computed tomography were used to acquire and segment the 3D cardiovascular anatomy. Models were fabricated by fused deposition modelling of polyurethane filament, and dimensions were compared with medical images. Decisions after the evaluation of routine clinical images were compared with those after inspection of the 3D model and intraoperative findings. Subjective satisfaction questionnaire was provided. RESULTS: 3D models accurately replicate anatomy with a mean bias of -0.27 ± 0.73 mm. Ninety-six percent of the surgeons agree or strongly agree that 3D models provided better understanding of CHD morphology and improved surgical planning. 3D models changed the surgical decision in 19 of the 40 cases. Consideration of a 3D model refined the planned biventricular repair, achieving an improved surgical correction in 8 cases. In 4 cases initially considered for conservative management or univentricular palliation, inspection of the 3D model enabled successful biventricular repair. CONCLUSIONS: 3D models are accurate replicas of the cardiovascular anatomy and improve the understanding of complex CHD. 3D models did not change the surgical decision in most of the cases (21 of 40 cases, 52.5% cases). However, in 19 of the 40 selected complex cases, 3D model helped redefining the surgical approach.

miR-125a, miR-139 and miR-324 contribute to Urocortin protection against myocardial ischemia-reperfusion injury.

Urocortin 1 and 2 (Ucn-1 and Ucn-2) have established protective actions against myocardial ischemia-reperfusion (I/R) injuries. However, little is known about their role in posttranscriptional regulation in the process of cardioprotection. Herein, we investigated whether microRNAs play a role in urocortin-induced cardioprotection. Administration of Ucn-1 and Ucn-2 at the beginning of reperfusion significantly restored cardiac function, as evidenced ex vivo in Langendorff-perfused rat hearts and in vivo in rat subjected to I/R. Experiments using microarray and qRT-PCR determined that the addition of Ucn-1 at reperfusion modulated the expression of several miRNAs with unknown role in cardiac protection. Ucn-1 enhanced the expression of miR-125a-3p, miR-324-3p; meanwhile it decreased miR-139-3p. Similarly, intravenous infusion of Ucn-2 in rat model of I/R mimicked the effect of Ucn-1 on miR-324-3p and miR-139-3p. The effect of Ucn-1 involves the activation of corticotropin-releasing factor receptor-2, Epac2 and ERK1/2. Moreover, the overexpression of miR-125a-3p, miR-324-3p and miR-139-3p promoted dysregulation of genes expression involved in cell death and apoptosis (BRCA1, BIM, STAT2), in cAMP and Ca2+ signaling (PDE4a, CASQ1), in cell stress (NFAT5, XBP1, MAP3K12) and in metabolism (CPT2, FoxO1, MTRF1, TAZ). Altogether, these data unveil a novel role of urocortin in myocardial protection, involving posttranscriptional regulation with miRNAs.

NT-proBNP as Marker of Ventricular Dilatation and Pulmonary Regurgitation After Surgical Correction of Tetralogy of Fallot: A MRI Validation Study.

The goal of this study is to evaluate whether NT-proBNP plasma levels may help as a screening biomarker for monitoring right ventricular dilatation, pulmonary regurgitation and the onset of heart failure in patients with repaired Tetralogy of Fallot. Our single-centre observational prospective study involved 43 patients (15.1 years, SD = 8) with corrected Tetralogy of Fallot. Data collection included: clinical parameters (electrocardiogram, chest X-ray, NYHA scale, time since last surgery), biochemistry (NT-proBNP levels) and MRI values (ventricular volumetry, pulmonary flow assessment). Mean time since last surgery was 13.5 years (SD = 7.8). There was a statistically significant correlation between the NT-proBNP levels (187.4 pg/ml, SD = 154.9) and right ventricular dilatation for both the right ventricular end-diastolic volume (124.9 ml/m2, SD = 31.2) (Pearson = 0.19, p < 0.01) and end-systolic volume (56.1 ml/m2, SD = 18.8) (Pearson = 0.21, p < 0.01) and also with the pulmonary regurgitation fraction (36.5%, SD = 16, Pearson = 0.12, p < 0.01). No significant correlation was found between NT-proBNP and right ventricular ejection fraction (54.6%, SD = 10.6, Pearson = -0.07), left ventricular ejection fraction (59.9%, SD = 7.1, Pearson = -0.18) or any clinical parameters. The receiver operating curve analysis evidenced that a NT-proBNP cut-off value above 133.2 pg/ml predicted the presence of dilated right ventricular end-diastolic and end-systolic volumes over centile 95 (sensitivity 82 and 83% and specificity 93 and 79%, respectively). In conclusion, in patients with surgically corrected Tetralogy of Fallot, NT-proBNP levels correlate with right ventricular dilatation and the degree of pulmonary regurgitation. Ambulatory determination of NT-proBNP might be an easy, readily available and cost-effective alternative for MRI follow-up evaluation of these patients.

Urocortin-1 Mediated Cardioprotection Involves XIAP and CD40-Ligand Recovery: Role of EPAC2 and ERK1/2.

AIMS: Urocortin-1 (Ucn-1) is an endogenous peptide that protects heart from ischemia and reperfusion (I/R) injuries. Ucn-1 is known to prevent cardiac cell death, but its role in the transcription of specific genes related to survival signaling pathway has not been fully defined. The aim of this study was to investigate the molecular signaling implicated in the improvement of cardiac myocytes survival induced by Ucn-1. METHODS AND RESULTS: Ucn-1 administration before ischemia and at the onset of reperfusion, in rat hearts perfused in Langendorff system, fully recovered heart contractility and other hemodynamic parameters. Ucn-1 enhanced cell viability and decreased lactate dehydrogenase (LDH) release in adult cardiac myocytes subjected to simulated I/R. Annexin V-FITC/PI staining indicated that Ucn-1 promoted cell survival and decreased cell necrosis through Epac2 (exchange protein directly activated by cAMP) and ERK1/2 (extracellular signal-regulated kinases 1/2) activation. We determined that Ucn-1 shifted cell death from necrosis to apoptosis and activated caspases 9 and 3/7. Furthermore, mini-array, RT-qPCR and protein analyses of apoptotic genes showed that Ucn-1 upregulated the expression of CD40lg, Xiap and BAD in cells undergoing I/R, involving Epac2 and ERK1/2 activation. CONCLUSIONS: Our data indicate that Ucn-1 efficiently protected hearts from I/R damage by increasing the cell survival and stimulated apoptotic genes, CD40lg, Xiap and BAD, overexpression through the activation of Epac2 and ERK1/2.

Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation.

AIMS: Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca(2+))-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca(2+) entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation. METHODS AND RESULTS: We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca(2+) mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca(2+) concentration ([Ca(2+)]i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd(3+)-sensitive current with similar features of the Ca(2+) release-activated Ca(2+) current (ICRAC). Additionally, UII stimulated VSMCs proliferation and Ca(2+)/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca(2+)/calmodulin-dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca(2+) influx, CREB activation and VSMCs proliferation. CONCLUSION: Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.

Surgical technique for heart transplantation: a strategy for congenital heart disease.

The standard techniques for orthotopic heart transplantation often require certain adjustments when the procedure is carried out for complex congenital heart disease. This is because of both the unusual anatomy and possible distortions caused by previous surgery. Such technical adjustments have been described in various published reports over the years. Those reports, when combined, do cover the full spectrum of the technical difficulties that may be encountered, whether the defects are in their original form or altered by surgery, such that no cardiac malformation or distortion would prohibit transplantation. However, those reports are comprehensive only when combined. None of the individual reports addresses all the possible technical challenges. Consequently, the available information is somewhat fragmented. In addition, the generic aspect of the described technical strategies is not always given the emphasis that it deserves. Indeed, occasionally a technique may be presented as a specific solution for a specific malformation, without necessarily pointing out that the same technique may be applied to other hearts with different overall pathologies but which share that specific malformation. The aim of this review article was to combine all the available published information in one article in a manner that constructs a simple but comprehensive and generic system of decision-making that may be applied to any heart in order to determine the exact technical adjustments needed for transplantation in each case. Such a strategy is possible for two reasons. First, only a few anatomical sites are technically significant, namely the points of anastomosis between the donor's organ and the recipient. The rest of the intracardiac morphology does not affect the operation and may be ignored. Second, each of those anatomical sites can present difficulties in only a few ways, and each of those few difficulties has a well-described and published solution already. Therefore, the exact technical adjustments required in each case may be worked out by the sequential assessment of the anastomotic sites alone.

[Radiological findings in patients with imported schistosomiasis]. / Hallazgos radiológicos en pacientes con esquistosomiasis importada.

INTRODUCTION: Imaging techniques, primarily ultrasound, are useful in the diagnosis and monitoring of patients with schistosomiasis in endemic areas. METHODS: Study of 219 patients treated in sub-Saharan Tropical Medicine Unit with a diagnosis of imported schistosomiasis by imaging techniques investigations including plain abdominal radiography and ultrasound. RESULTS: A total of 17.8% of patients who had an abdominal X-ray showed findings suggestive of schistosomiasis, in most cases bladder calcifications. In 73 patients (41%) ultrasound showed pathological findings, mainly diffuse or focal wall thickening (26 patients), nodular lesions (n=14), and pseudopolyps (n=8). One patient, who had a large bladder mass (9cm) and bilateral ureterohydronephrosis, was finally diagnosed with squamous cell carcinoma of the bladder. Ultrasound liver abnormalities were found in 10 patients, 4 with signs of portal hypertension, of which 3 had the characteristic periportal fibrosis in schistosomiasis. CONCLUSION: Imaging studies, especially abdominal and bladder ultrasound, are useful for diagnosis, the study of disease and monitoring of patients with schistosomiasis in non-endemic countries.